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  • 1. Bergman, P.
    et al.
    Esfahani, Shiva Seyedoleslami
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Engström, Ylva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Drosophila as a Model for Human Diseases-Focus on Innate Immunity in Barrier Epithelia2017In: Fly Models of Human Diseases / [ed] Leslie Pick, San Diego, CA: Elsevier, 2017, Vol. 121, p. 29-81Chapter in book (Refereed)
    Abstract [en]

    Epithelial immunity protects the host from harmful microbial invaders but also controls the beneficial microbiota on epithelial surfaces. When this delicate balance between pathogen and symbiont is disturbed, clinical disease often occurs, such as in inflammatory bowel disease, cystic fibrosis, or atopic dermatitis, which all can be in part linked to impairment of barrier epithelia. Many innate immune receptors, signaling pathways, and effector molecules are evolutionarily conserved between human and Drosophila. This review describes the current knowledge on Drosophila as a model for human diseases, with a special focus on innate immune-related disorders of the gut, lung, and skin. The discovery of antimicrobial peptides, the crucial role of Toll and Toll-like receptors, and the evolutionary conservation of signaling to the immune systems of both human and Drosophila are described in a historical perspective. Similarities and differences between human and Drosophila are discussed; current knowledge on receptors, signaling pathways, and effectors are reviewed, including antimicrobial peptides, reactive oxygen species, as well as autophagy. We also give examples of human diseases for which Drosophila appears to be a useful model. In addition, the limitations of the Drosophila model are mentioned. Finally, we propose areas for future research, which include using the Drosophila model for drug screening, as a validation tool for novel genetic mutations in humans and for exploratory research of microbiota-host interactions, with relevance for infection, wound healing, and cancer.

  • 2.
    Dantoft, Widad
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Buchon, Nicolas
    Lemaitre, Bruno
    Engström, Ylva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Signal-dependent degradation of the Oct/POU protein Nubbin in response to infectionManuscript (preprint) (Other academic)
  • 3.
    Dantoft, Widad
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Davis, Monica M.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lindvall, Jessica M.
    Tang, Xiongzhuo
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Uvell, Hanna
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Junell, Anna
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Beskow, Anne
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Engström, Ylva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    The Oct1 homolog Nubbin is a repressor of NF-kappa B-dependent immune gene expression that increases the tolerance to gut microbiota2013In: BMC Biology, ISSN 1741-7007, E-ISSN 1741-7007, Vol. 11, article id 99Article in journal (Refereed)
    Abstract [en]

    Background: Innate immune responses are evolutionarily conserved processes that provide crucial protection against invading organisms. Gene activation by potent NF-kappa B transcription factors is essential both in mammals and Drosophila during infection and stress challenges. If not strictly controlled, this potent defense system can activate autoimmune and inflammatory stress reactions, with deleterious consequences for the organism. Negative regulation to prevent gene activation in healthy organisms, in the presence of the commensal gut flora, is however not well understood. Results: We show that the Drosophila homolog of mammalian Oct1/POU2F1 transcription factor, called Nubbin (Nub), is a repressor of NF-kappa B/Relish-driven antimicrobial peptide gene expression in flies. In nub(1) mutants, which lack Nub-PD protein, excessive expression of antimicrobial peptide genes occurs in the absence of infection, leading to a significant reduction of the numbers of cultivatable gut commensal bacteria. This aberrant immune gene expression was effectively blocked by expression of Nub from a transgene. We have identified an upstream regulatory region, containing a cluster of octamer sites, which is required for repression of antimicrobial peptide gene expression in healthy flies. Chromatin immunoprecipitation experiments demonstrated that Nub binds to octamer-containing promoter fragments of several immune genes. Gene expression profiling revealed that Drosophila Nub negatively regulates many genes that are involved in immune and stress responses, while it is a positive regulator of genes involved in differentiation and metabolism. Conclusions: This study demonstrates that a large number of genes that are activated by NF-kappa B/Relish in response to infection are normally repressed by the evolutionarily conserved Oct/POU transcription factor Nub. This prevents uncontrolled gene activation and supports the existence of a normal gut flora. We suggest that Nub protein plays an ancient role, shared with mammalian Oct/POU transcription factors, to moderate responses to immune challenge, thereby increasing the tolerance to biotic stress.

  • 4.
    Dantoft, Widad
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lundin, Daniel
    Engström, Ylva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    The POU/Oct transcription factor Nubbin is necessary for a beneficial gut microbiome and for normal lifespan of DrosophilaManuscript (preprint) (Other academic)
  • 5.
    Dantoft, Widad
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lundin, Daniel
    Esfahani, Shiva Seyedoleslami
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Engström, Ylva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    The POU/Oct Transcription Factor Pdm1/nub Is Necessary for a Beneficial Gut Microbiota and Normal Lifespan of Drosophila2016In: Journal of Innate Immunity, ISSN 1662-811X, E-ISSN 1662-8128, Vol. 8, no 4, p. 412-426Article in journal (Refereed)
    Abstract [en]

    Maintenance of a stable gut microbial community relies on a delicate balance between immune defense and immune tolerance. We have used Drosophila to study how the microbial gut flora is affected by changes in host genetic factors and immunity. Flies with a constitutively active gut immune system, due to a mutation in the POU transcriptional regulator Pdm1/nubbin (nub) gene, had higher loads of bacteria and a more diverse taxonomic composition than controls. In addition, the microbial composition shifted considerably during the short lifespan of the nub(1) mutants. This shift was characterized by a loss of relatively few OTUs (operational taxonomic units) and a remarkable increase in a large number of Acetobacter spp. and Leuconostoc spp. Treating nub(1) mutant flies with antibiotics prolonged their lifetime survival by more than 100%. Immune gene expression was also persistently high in the presence of antibiotics, indicating that the early death was not a direct consequence of an over-active immune defense but rather an indirect consequence of the microbial load and composition. Thus, changes in host genotype and an inability to regulate the normal growth and composition of the gut microbiota leads to a shift in the microbial community, dysbiosis and early death.

  • 6.
    Davis, Monica M.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Alvarez, Francisco J.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Ryman, Kicki
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Holm, Åsa A.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Ljungdahl, Per O.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Cell Biology.
    Engström, Ylva
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Wild-Type Drosophila melanogaster as a Model Host to Analyze Nitrogen Source Dependent Virulence of Candida albicans2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 11, p. e27434-Article in journal (Refereed)
    Abstract [en]

    The fungal pathogen Candida albicans is a common cause of opportunistic infections in humans. We report that wild-type Drosophila melanogaster (OrR) flies are susceptible to virulent C. albicans infections and have established experimental conditions that enable OrR flies to serve as model hosts for studying C. albicans virulence. After injection into the thorax, wild-type C. albicans cells disseminate and invade tissues throughout the fly, leading to lethality. Similar to results obtained monitoring systemic infections in mice, well-characterized cph1Δ efg1Δ and csh3Δ fungal mutants exhibit attenuated virulence in flies. Using the OrR fly host model, we assessed the virulence of C. albicans strains individually lacking functional components of the SPS sensing pathway. In response to extracellular amino acids, the plasma membrane localized SPS-sensor (Ssy1, Ptr3, and Ssy5) activates two transcription factors (Stp1 and Stp2) to differentially control two distinct modes of nitrogen acquisition (host protein catabolism and amino acid uptake, respectively). Our results indicate that a functional SPS-sensor and Stp1 controlled genes required for host protein catabolism and utilization, including the major secreted aspartyl protease SAP2, are required to establish virulent infections. By contrast, Stp2, which activates genes required for amino acid uptake, is dispensable for virulence. These results indicate that nutrient availability within infected hosts directly influences C. albicans virulence.

  • 7.
    Davis, Monica M.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Engström, Ylva
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Immune Response in the Barrier Epithelia: Lessons from the Fruit Fly Drosophila melanogaster2012In: Journal of innate immunity, ISSN 1662-811X, Vol. 4, no 3, p. 273-283Article, review/survey (Refereed)
    Abstract [en]

    The barrier epithelia of multicellular organisms frequently come into direct contact with microorganisms and thus need to fulfill the important task of preventing the penetration of pathogens that could cause systemic infections. A functional immune defence in the epithelial linings of the digestive, respiratory and reproductive organs as well as the epidermis/skin of animals is therefore of crucial importance for survival. Epithelial defence reactions are likely to be evolutionarily ancient, and the use of invertebrate animal models, such as insects and nematodes, has been crucial in unravelling the mechanisms underlying epithelial immunity. This review addresses basic questions of epithelial immunity in animals and humans. It focuses on recent developments in the understanding of the immune responses in the fruit fly Drosophila melanogaster and how the innate immune system acts locally in the epidermis and cuticle, tracheae, gut and genital organs. Both basal immune activities in epithelia that are constantly exposed to microbes as well as positive and negative regulation in response to pathogenic organisms are covered. Important immuno-physiological aspects of epithelial defence mechanisms are also discussed, such as wound healing, re-epithelialization and intestinal homeostasis. 

  • 8. Delaney, J R
    et al.
    Stöven, S
    Uvell, H
    Anderson, K V
    Engström, Y
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Mlodzik, M
    Cooperative control of Drosophila immune responses by the JNK and NF-kB signaling pathways2006In: The EMBO Journal, Vol. 25, p. 3068-3077Article in journal (Refereed)
  • 9.
    Engström, Y
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Loseva, O
    Theopold, U
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Proteomics of the Drosophila immune response2004In: Trends in Biotechnology, Vol. 22, no 11, p. 600-605Article in journal (Refereed)
  • 10.
    Esfahani, Shiva Seyedoleslami
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Engström, Ylva
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Activation of an innate immune response in large numbers of permeabilized Drosophila embryos2011In: Developmental and Comparative Immunology, ISSN 0145-305X, E-ISSN 1879-0089, Vol. 35, no 3, p. 263-266Article in journal (Refereed)
    Abstract [en]

    Innate immunity in Drosophila involves the inducible expression and synthesis of antimicrobial peptides. We have previously shown that not only Drosophila larvae and adults, but also embryos, are capable of mounting an immune response after injection of bacterial substances. To simplify genetic dissection of the signaling pathways involved in immune-gene regulation we developed a procedure for permeabilization of large number of embryos and subsequent infiltration with bacterial fragments. This approach, which promoted expression of CecropinA1- and Diptericin-driven β-gal expression in the epidermis of more than 90% of the treated embryos, will enable analysis of mutants that are embryonic lethal. Thus, genes that are involved in essential pleiotrophic functions, in addition to being candidates in immune-regulation will be amenable for analysis of their involvement in the fly's immune defense.

  • 11. Junell, Anna
    et al.
    Uvell, Hanna
    Davis, Monica M
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Edlundh-Rose, Esther
    Antonsson, Åsa
    Pick, Leslie
    Engström, Ylva
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    The POU Transcription Factor Drifter/Ventral veinless Regulates Expression of Drosophila Immune Defence Genes2010In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 30, no 14, p. 3672-3684Article in journal (Other academic)
    Abstract [en]

    Innate immunity operates as a first line of defense in multicellular organisms against infections caused by different classes of microorganisms. Antimicrobial peptides (AMPs) are synthesized constitutively in barrier epithelia to protect against microbial attack and are also upregulated in response to infection. Here, we implicate Drifter/Ventral veinless (Dfr/Vvl), a class III POU domain transcription factor, in tissue-specific regulation of the innate immune defense of Drosophila. We show that Dfr/Vvl is highly expressed in a range of immunocompetent tissues, including the male ejaculatory duct, where its presence overlaps with and drives the expression of cecropin, a potent broad-spectrum AMP. Dfr/Vvl overexpression activates transcription of several AMP genes in uninfected flies in a Toll pathway- and Imd pathway-independent manner. Dfr/Vvl activates a CecA1 reporter gene both in vitro and in vivo by binding to an upstream enhancer specific for the male ejaculatory duct. Further, Dfr/Vvl and the homeodomain protein Caudal (Cad) activate transcription synergistically via this enhancer. We propose that the POU protein Dfr/Vvl acts together with other regulators in a combinatorial manner to control constitutive AMP gene expression in a gene-, tissue-, and sex-specific manner, thus promoting a first-line defense against infection in tissues that are readily exposed to pathogens.

  • 12.
    Junell, Anna
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Uvell, Hanna
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Pick, Leslie
    Engström, Ylva
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Isolation of regulators of Drosophila immune defense genes by a double interaction screen in yeast2007In: Insect Biochemistry and Molecular Biology, ISSN 0965-1748, E-ISSN 1879-0240, Vol. 37, no 3, p. 202-212Article in journal (Refereed)
    Abstract [en]

    Innate immunity is a universal and ancient defense system in metazoans against microorganisms. Antimicrobial peptides, which are synthesized both in insects and humans, constitute an endogenous, gene-encoded defense arsenal. In Drosophila, antimicrobial peptides, such as the potent cecropins, are expressed both constitutively in barrier epithelia, as well as systemically in response to infection. Rel/NF-κB proteins are well-known regulators of antimicrobial peptide genes, but very few Rel/NF-κB co-factors and/or tissue-specific regulators have been identified. We performed a double interaction screen in yeast to isolate Drosophila cDNAs coding for direct regulators, as well as Dif co-regulators, of the CecropinA1 gene. Three classes of positive cDNA clones corresponding to 15 Drosophila genes were isolated and further characterized. One of the Dif-independent cDNAs encoded the Rel/NF-κB protein Relish; a well-known activator of antimicrobial peptide genes in Drosophila, demonstrating the applicability of this type of screen for isolating regulators of immune defense. Most interestingly, three transcription factors belonging to the POU domain class of homeodomain proteins, Pdm1, Pdm2 and Dfr/Vvl were isolated as Dif-interacting partners, and subsequently verified as regulators of CecA1 expression in Drosophila cells. The importance of POU proteins in development and differentiation in Drosophila and mammals is well documented, but their role in regulation of Drosophila immune defense genes is a new and essential finding.

  • 13.
    Lindberg, Bo G.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Tang, Xiongzhuo
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Dantoft, Widad
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Gohel, Priya
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Seyedoleslami Esfahani, Shiva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lindvall, Jessica M.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Engström, Ylva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nubbin isoform antagonism governs Drosophila intestinal immune homeostasis2018In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 14, no 3, article id e1006936Article in journal (Refereed)
    Abstract [en]

    Gut immunity is regulated by intricate and dynamic mechanisms to ensure homeostasis despite a constantly changing microbial environment. Several regulatory factors have been described to participate in feedback responses to prevent aberrant immune activity. Little is, however, known about how transcriptional programs are directly tuned to efficiently adapt host gut tissues to the current microbiome. Here we show that the POU/Oct gene nubbin (nub) encodes two transcription factor isoforms, Nub-PB and Nub-PD, which antagonistically regulate immune gene expression in Drosophila. Global transcriptional profiling of adult flies overexpressing Nub-PB in immunocompetent tissues revealed that this form is a strong transcriptional activator of a large set of immune genes. Further genetic analyses showed that Nub-PB is sufficient to drive expression both independently and in conjunction with nuclear factor kappa B (NF-κB), JNK and JAK/STAT pathways. Similar overexpression of Nub-PD did, conversely, repress expression of the same targets. Strikingly, isoform co-overexpression normalized immune gene transcription, suggesting antagonistic activities. RNAi-mediated knockdown of individual nub transcripts in enterocytes confirmed antagonistic regulation by the two isoforms and that both are necessary for normal immune gene transcription in the midgut. Furthermore, enterocyte-specific Nub-PB expression levels had a strong impact on gut bacterial load as well as host lifespan. Overexpression of Nub-PB enhanced bacterial clearance of ingested Erwinia carotovora carotovora 15. Nevertheless, flies quickly succumbed to the infection, suggesting a deleterious immune response. In line with this, prolonged overexpression promoted a proinflammatory signature in the gut with induction of JNK and JAK/STAT pathways, increased apoptosis and stem cell proliferation. These findings highlight a novel regulatory mechanism of host-microbe interactions mediated by antagonistic transcription factor isoforms.

  • 14. Lindmark, Hans
    et al.
    Johansson, Karin C
    Stöven, Svenja
    Hultmark, Dan
    Engström, Ylva
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Söderhäll, Kenneth
    Enteric bacteria Counteract Lipopolysaccharide Induction of Antimicrobial Peptide Genes2001In: The Journal of Immunology, Vol. 167, p. 6920-6923Article in journal (Refereed)
  • 15. Liu, Ning-Ning
    et al.
    Uppuluri, Priya
    Broggi, Achille
    Besold, Angelique
    Ryman, Kicki
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kambara, Hiroto
    Solis, Norma
    Lorenz, Viola
    Qi, Wanjun
    Acosta-Zaldívar, Maikel
    Emami, S. Noushin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Bao, Bin
    An, Dingding
    Bonilla, Francisco A.
    Sola-Visner, Martha
    Filler, Scott G.
    Luo, Hongbo R.
    Engström, Ylva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Ljungdahl, Per Olof
    Culotta, Valeria C.
    Zanoni, Ivan
    Lopez-Ribot, Jose L.
    Köhler, Julia R.
    Intersection of phosphate transport, oxidative stress and TOR signalling in Candida albicans virulence2018In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 14, no 7, article id e1007076Article in journal (Refereed)
    Abstract [en]

    Phosphate is an essential macronutrient required for cell growth and division. Pho84 is the major high-affinity cell-surface phosphate importer of Saccharomyces cerevisiae and a crucial element in the phosphate homeostatic system of this model yeast. We found that loss of Candida albicans Pho84 attenuated virulence in Drosophila and murine oropharyngeal and disseminated models of invasive infection, and conferred hypersensitivity to neutrophil killing. Susceptibility of cells lacking Pho84 to neutrophil attack depended on reactive oxygen species (ROS): pho84-/- cells were no more susceptible than wild type C. albicans to neutrophils from a patient with chronic granulomatous disease, or to those whose oxidative burst was pharmacologically inhibited or neutralized. pho84-/- mutants hyperactivated oxidative stress signalling. They accumulated intracellular ROS in the absence of extrinsic oxidative stress, in high as well as low ambient phosphate conditions. ROS accumulation correlated with diminished levels of the unique superoxide dismutase Sod3 in pho84-/- cells, while SOD3 overexpression from a conditional promoter substantially restored these cells' oxidative stress resistance in vitro. Repression of SOD3 expression sharply increased their oxidative stress hypersensitivity. Neither of these oxidative stress management effects of manipulating SOD3 transcription was observed in PHO84 wild type cells. Sod3 levels were not the only factor driving oxidative stress effects on pho84-/- cells, though, because overexpressing SOD3 did not ameliorate these cells' hypersensitivity to neutrophil killing ex vivo, indicating Pho84 has further roles in oxidative stress resistance and virulence. Measurement of cellular metal concentrations demonstrated that diminished Sod3 expression was not due to decreased import of its metal cofactor manganese, as predicted from the function of S. cerevisiae Pho84 as a low-affinity manganese transporter. Instead of a role of Pho84 in metal transport, we found its role in TORC1 activation to impact oxidative stress management: overexpression of the TORC1-activating GTPase Gtr1 relieved the Sod3 deficit and ROS excess in pho84-/- null mutant cells, though it did not suppress their hypersensitivity to neutrophil killing or hyphal growth defect. Pharmacologic inhibition of Pho84 by small molecules including the FDA-approved drug foscarnet also induced ROS accumulation. Inhibiting Pho84 could hence support host defenses by sensitizing C. albicans to oxidative stress.

  • 16. Llopis-Torregrosa, Vicent
    et al.
    Vaz, Catarina
    Monteoliva, Lucia
    Ryman, Kicki
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Engström, Ylva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Gacser, Attila
    Gil, Concha
    Ljungdahl, Per O.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sychrova, Hana
    Trk1-mediated potassium uptake contributes to cell-surface properties and virulence of Candida glabrata2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 7529Article in journal (Refereed)
    Abstract [en]

    The absence of high-affinity potassium uptake in Candida glabrata, the consequence of the deletion of the TRK1 gene encoding the sole potassium-specific transporter, has a pleiotropic effect. Here, we show that in addition to changes in basic physiological parameters (e.g., membrane potential and intracellular pH) and decreased tolerance to various cell stresses, the loss of high affinity potassium uptake also alters cell-surface properties, such as an increased hydrophobicity and adherence capacity. The loss of an efficient potassium uptake system results in diminished virulence as assessed by two insect host models, Drosophila melanogaster and Galleria mellonella, and experiments with macrophages. Macrophages kill trk1 Delta cells more effectively than wild type cells. Consistently, macrophages accrue less damage when co-cultured with trk1 Delta mutant cells compared to wild-type cells. We further show that low levels of potassium in the environment increase the adherence of C. glabrata cells to polystyrene and the propensity of C. glabrata cells to form biofilms.

  • 17. Loseva, O
    et al.
    Engström, Y
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Analysis of Signal-dependent Changes in the Proteome of Drosophila Blood Cells During an Immune Response2004In: Molecular and Cellular Proteomics, Vol. 3, no 8, p. 796-808Article in journal (Refereed)
  • 18. Miele, Rosella
    et al.
    Björklund, Gunnel
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Barra, Donatella
    Simmaco, Maurizio
    Engström, Ylva
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Involvement of Rel factors in the expression of antimicrobial peptide genes in amphibia2001In: European Journal of Biochermistry, Vol. 268, p. 443-449Article in journal (Refereed)
  • 19. O'Farrell, Fergal
    et al.
    Seyedoleslami Esfahani, Shiva
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Engström, Ylva
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Kylsten, Per
    Regulation of the Drosophila lin-41 Homologue dappled by let-7 Reveals Conservation of a Regulatory Mechanism Within the LIN-41 Subclade2008In: Developmental Dynamics, ISSN 1058-8388, E-ISSN 1097-0177, Vol. 237, no 1, p. 196-208Article in journal (Refereed)
    Abstract [en]

    Drosophila Dappled (DPLD) is a member of the RBCC/TRIM superfamily, a protein family involved in numerous diverse processes such as developmental timing and asymmetric cell divisions. DPLD belongs to the LIN-41 subclade, several members of which are micro RNA (miRNA) regulated. We re-examined the LIN-41 subclade members and their relation to other RBCC/TRIMs and dpld paralogs, and identified a new Drosophila muscle specific RBCC/TRIM: Another B-Box Affiliate, ABBA. In silico predictions of candidate miRNA regulators of dpld identified let-7 as the strongest candidate. Overexpression of dpld led to abnormal eye development, indicating that strict regulation of dpld mRNA levels is crucial for normal eye development. This phenotype was sensitive to let-7 dosage, suggesting let-7 regulation of dpld in the eye disc. A cell-based assay verified let-7 miRNA down-regulation of dpld expression by means of its 3′-untranslated region. Thus, dpld seems also to be miRNA regulated, suggesting that miRNAs represent an ancient mechanism of LIN-41 regulation.

  • 20. Papadopoulos, Dimitrios K.
    et al.
    Skouloudaki, Kassiani
    Engström, Ylva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Terenius, Lars
    Rigler, Rudolf
    Zechner, Christoph
    Vukojević, Vladana
    Tomancak, Pavel
    Control of Hox transcription factor concentration and cell-to-cell variability by an auto-regulatory switch2019In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 146, no 12, article id UNSP dev168179Article in journal (Refereed)
    Abstract [en]

    The variability in transcription factor concentration among cells is an important developmental determinant, yet how variability is controlled remains poorly understood. Studies of variability have focused predominantly on monitoring mRNA production noise. Little information exists about transcription factor protein variability, as this requires the use of quantitative methods with single-molecule sensitivity. Using Fluorescence Correlation Spectroscopy (FCS), we have characterized the concentration and variability of 14 endogenously tagged TFs in live Drosophila imaginal discs. For the Hox TF Antennapedia, we investigated whether protein variability results from random stochastic events or is developmentally regulated. We found that Antennapedia transitioned from low concentration/high variability early, to high concentration/low variability later, in development. FCS and temporally resolved genetic studies uncovered that Antennapedia itself is necessary and sufficient to drive a developmental regulatory switch from auto-activation to auto-repression, thereby reducing variability. This switch is controlled by progressive changes in relative concentrations of preferentially activating and repressing Antennapedia isoforms, which bind chromatin with different affinities. Mathematical modeling demonstrated that the experimentally supported auto-regulatory circuit can explain the increase of Antennapedia concentration and suppression of variability over time.

  • 21. Roxström-Lindquist, K
    et al.
    Lindström-Dinnetz, I
    Olesen, J
    Engström, Y
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Faye, I
    An intron enhancer activates the immunoglobulin-related Hemolin gene in Hyalophora cecropia2002In: Insect Molecular Biology, ISSN 09621075, Vol. 11, p. 505-515Article in journal (Refereed)
  • 22.
    Seyedoleslami Esfahani, Shiva
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Önfelt Tingvall, Tove
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Björklund, Gunnel
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Engström, Ylva
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Nuclear localization of the Drosophila IκB protein Cactus and its response to the Toll signaling pathwayManuscript (preprint) (Other academic)
    Abstract [en]

    In Drosophila, the Toll signaling pathway is known as a regulator of both dorso-ventral patterning during embryogenesis and regulation of immunity. Activation of of the Toll pathway results in nuclear accumulation of the NFκB/Rel transcription factors Dif and Dorsal, and the subsequent activation of downstream target genes. The current model is that Cactus is a strictly cytoplasmic protein, interacting with Dorsal and Dif to inhibit their nuclear translocation. However, immunostaining revealed that Cactus is present both in the nucleus and cytoplasm of fat body cells and S2 cells. Activation of Toll signaling in cell culture demonstrated that a nuclear form of Cactus is stable and persists during signaling, while cytoplasmic Cactus is degraded in a proteosome-dependent manner and then re-synthesized. Alternative splicing of Cactus pre-mRNA produces two Cactus isoforms, differing by 18 amino acids in the C-terminus. We show that both isoforms act as inhibotors of Dif- and Dorsal-mediated Drosomycin-luciferase expression, although the longer isoform of Cactus was a slightly better inhibitor. Both isoforms showed similar subcellular distribution, being present both in the cytoplasm and nucleus of larval fat body cells. Thus, the present finding suggest that Cactus does not act as a degradeable, cytoplasmic inhibitor of Dif and Dorsal, but also plays a role in the nucleus during immune challenge. 

  • 23. Stöven, Svenja
    et al.
    Silverman, Neil
    Junell, Anna
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Hedengren-Olcott, Marika
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Erturk, Deniz
    Engström, Ylva
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Maniatis, Tom
    Hultmark, Dan
    Caspase-mediated processing of the Drosophila NF-κB factor Relish2003In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 100, no 10, p. 5991-5996Article in journal (Refereed)
    Abstract [en]

    The NF-κB-like transcription factor Relish plays a central role in the innate immune response of Drosophila. Unlike other NF-κB proteins, Relish is activated by endoproteolytic cleavage to generate a DNA-binding Rel homology domain and a stable IκB-like fragment. This signal-induced endoproteolysis requires the activity of several gene products, including the IκB kinase complex and the caspase Dredd. Here we used mutational analysis and protein microsequencing to demonstrate that a caspase target site, located in the linker region between the Rel and the IκB-like domain, is the site of signal-dependent cleavage. We also show physical interaction between Relish and Dredd, suggesting that Dredd indeed is the Relish endoprotease. In addition to the caspase target site, the C-terminal 107 aa of Relish are required for endoproteolysis and signal-dependent phosphorylation by the Drosophila IκB kinase β. Finally, an N-terminal serine-rich region in Relish and the PEST domain were found to negatively regulate Relish activation.

  • 24.
    Tang, Xiongzhuo
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Engström, Ylva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Regulation of immune and tissue homeostasis by Drosophila POU factors2019In: Insect Biochemistry and Molecular Biology, ISSN 0965-1748, E-ISSN 1879-0240, Vol. 109, p. 24-30Article in journal (Refereed)
    Abstract [en]

    The innate immune system of insects deploys both cellular and humoral reactions in immunocompetent tissues for protection of insects against a variety of infections, including bacteria, fungi, and viruses. Transcriptional regulation of genes encoding antimicrobial peptides (AMPs), cytokines, and other immune effectors plays a pivotal role in maintenance of immune homeostasis both prior to and after infections. The POU/Oct transcription factor family is a subclass of the homeodomain proteins present in all metazoans. POU factors are involved in regulation of development, metabolism and immunity. Their role in regulation of immune functions has recently become evident, and involves control of tissue-specific, constitutive expression of immune effectors in barrier epithelia as well as positive and negative control of immune responses in gut and fat body. In addition, they have been shown to affect the composition of gut microbiota and play a role in regulation of intestinal stem cell activities. In this review, we summarize the current knowledge of how POU transcription factors control Drosophila immune homeostasis in healthy and infected insects. The role of POU factor isoform specific regulation of stem cell activities in Drosophila and mammals is also discussed.

  • 25.
    Tang, Xiongzhuo
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Gohel, Priya
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Engström, Ylva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Characterization of the role of Nub-PB in gut epithelium regenerationManuscript (preprint) (Other academic)
    Abstract [en]

    The gene for Drosophila POU/Oct transcription factor Nubbin (Nub)/Pdm1 encodes two independent isoforms, Nub-PB and Nub-PD, which act antagonistically in gut progenitor cells to maintain normal intestinal stem cell (ISC) proliferation. However, the role of Nub-PB in regulating midgut epithelium regeneration is not fully understood.  Here, we have created a viable nub mutant named nubPB-3 and find that this mutant displays shortened adult lifespan in normal rearing conditions. Careful analysis of nubPB-3 midgut morphology revealed an enlarged anterior midgut with increased ISC proliferation, enhanced enteroendocrine (EE) lineage differentiation and enforced delamination of enterocytes (ECs). Furthermore, we found that the increased ISC proliferation in the nubPB-3 mutant is caused by the high activity of JAK/STAT signaling in the anterior midgut, indicating that Nub-PB normally represses the JAK/STAT activity in progenitor cells. A high rate of ISC proliferation caused by oral Ecc15 infection was, however, not dependent on Nub-PB.  This suggests a role for Nub-PB in suppressing the rate of ISC proliferation under normal conditions, a role which is lost during infection-induced proliferation. Interestingly, nubPB-3 mutants were susceptible to Ecc15 infection and died shortly thereafter. While this was not due to gut epithelium leakage or impaired antimicrobial peptide gene expression, a more general failure in gut physiology, digestion and metabolism may be the underlying cause of death.

  • 26.
    Tang, Xiongzhuo
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Zhao, Yunpo
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Buchon, Nicolas
    Engström, Ylva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    The POU/Oct Transcription Factor Nubbin Controls the Balance of Intestinal Stem Cell Maintenance and Differentiation by Isoform-Specific Regulation2018In: Stem Cell Reports, ISSN 2213-6711, Vol. 10, no 5, p. 1565-1578Article in journal (Refereed)
    Abstract [en]

    Drosophila POU/Oct transcription factors are required for many developmental processes, but their putative regulation of adult stem cell activity has not been investigated. Here, we show that Nubbin (Nub)/Pdm1, homologous to mammalian OCT1/POU2F1 and related to OCT4/POU5F1, is expressed in gut epithelium progenitor cells. We demonstrate that the nub-encoded protein isoforms, Nub-PB and Nub-PD, play opposite roles in the regulation of intestinal stem cell (ISC) maintenance and differentiation. Depletion of Nub-PB in progenitor cells increased ISC proliferation by derepression of escargot expression. Conversely, loss of Nub-PD reduced ISC proliferation, suggesting that this isoform is necessary for ISC maintenance, analogous to mammalian OCT4/POU5F1 functions. Furthermore, Nub-PB is required in enteroblasts to promote differentiation, and it acts as a tumor suppressor of Notch RNAi-driven hyperplasia. We suggest that a dynamic and well-tuned expression of Nub isoforms in progenitor cells is required for maintaining gut epithelium homeostasis.

  • 27. Uvell, H
    et al.
    Engström, Y
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Functional Characterization of a Novel Promoter Element Required for an Innate Immune Response in Drosophila2003In: Molecular and Cellular Biology, p. 8272-8281Article in journal (Refereed)
  • 28. Valanne, Susanna
    et al.
    Myllymäki, Henna
    Kallio, Jenni
    Schmid, Martin Rudolf
    Kleino, Anni
    Murumägi, Astrid
    Airaksinen, Laura
    Kotipelto, Tapio
    Kaustio, Meri
    Ulvila, Johanna
    Esfahani, Shiva Seyedoleslami
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Engström, Ylva
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Silvennoinen, Olli
    Hultmark, Dan
    Parikka, Mataleena
    Rämet, Mika
    Genome-Wide RNA Interference in Drosophila Cells Identifies G Protein-Coupled Receptor Kinase 2 as a Conserved Regulator of NF-kappa B Signaling2010In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 184, no 11, p. 6188-6198Article in journal (Refereed)
    Abstract [en]

    Because NF-kappa B signaling pathways are highly conserved in evolution, the fruit fly Drosophila melanogaster provides a good model to study these cascades. We carried out an RNA interference (RNAi)-based genome-wide in vitro reporter assay screen in Drosophila for components of NF-kappa B pathways. We analyzed 16,025 dsRNA-treatments and identified 10 novel NF-kappa B regulators. Of these, nine dsRNA-treatments affect primarily the Toll pathway. G protein-coupled receptor kinase (Gprk) 2, CG15737/Toll pathway activation mediating protein, and u-shaped were required for normal Drosomycin response in vivo. Interaction studies revealed that Gprk2 interacts with the Drosophila I kappa B homolog Cactus, but is not required in Cactus degradation, indicating a novel mechanism for NF-kappa B regulation. Morpholino silencing of the zebrafish ortholog of Gprk2 in fish embryos caused impaired cytokine expression after Escherichia coli infection, indicating a conserved role in NF-kappa B signaling. Moreover, small interfering RNA silencing of the human ortholog GRK5 in HeLa cells impaired NF-kappa B reporter activity. Gprk2 RNAi flies are susceptible to infection with Enterococcus faecalis and Gprk2 RNAi rescues Toll(10b)-induced blood cell activation in Drosophila larvae in vivo. We conclude that Gprk2/GRK5 has an evolutionarily conserved role in regulating NF-kappa B signaling. The Journal of Immunology, 2010, 184: 6188-6198.

  • 29. Önfelt Tingvall, Tove
    et al.
    Roos, Erik
    Engström, Ylva
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    The GATA factor Serpent is required for the onset of the humoral immune response in Drosophila embyos2001In: Proc. Natl. Acad. Sci., Vol. 98, p. 3884-3888Article in journal (Refereed)
  • 30. Önfelt Tingvall, Tove
    et al.
    Roos, Erik
    Engström, Ylva
    Stockholm University.
    The imd gene is required for local Cecropin expression in Drosophila barrier epithelia2001In: EMBO reports, Vol. 2, no 3, p. 239-243Article in journal (Other (popular science, discussion, etc.))
1 - 30 of 30
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