Impairment of Mycobacterial But Not Viral Immunity by a Germline Human
            <i>STAT1</i>
            Mutation

Dupuis, Stéphanie; Dargemont, Catherine; Fieschi, Claire; Thomassin, Nicolas; Rosenzweig, Sergio D.; Harris, Jeff; Holland, Steven M.; Schreiber, Robert D.; Casanova, Jean‐Laurent

doi:10.1126/science.1061154

Cited by 476 publications

(367 citation statements)

References 22 publications

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“…These have been shown to include epidermal growth factor, M-CSF, IL-6, IL-10, and others (71-74). STAT1-deficient mice show a normal responsiveness to these other cytokines, whereas both IFN-␣-and IFN-␥-signaling was impaired, indicating that STAT1 is a transcription factor dedicated to IFN signaling (56,57,75). The basis for the differential effect of PIASy on signaling by IFN-␣ and IFN-␥ is unclear but it may be related to the cross-talk between these signaling pathways (6).…”

Section: Discussionmentioning

confidence: 98%

PIASy-Deficient Mice Display Modest Defects in IFN and Wnt Signaling

Roth

Sustmann

Kieslinger

et al. 2004

The Journal of Immunology

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Protein inhibitors of activated STATs (PIAS) represent a small family of nuclear proteins that modulate the activity of many transcription factors and act as E3 ligases for covalent modification of proteins with the small ubiquitin-like modifier (SUMO). In particular, PIASy has been shown to inhibit the activation of gene expression by the IFN-responsive transcription factor STAT1 and the Wnt-responsive transcription factor LEF1. To assess the function of PIASy in vivo, we generated and analyzed mice carrying a targeted mutation of the Piasy gene. We find that homozygous mutant mice have no obvious morphological defects and have a normal distribution of lymphocyte populations. Molecular analysis of signaling in response to IFN-γ and Wnt agonists revealed a modest reduction in the activation of endogenous and transfected target genes. Two-dimensional analysis of total proteins and SUMO-modified proteins in transformed pre-B cells showed no significant differences between wild-type mice and homozygous mutant mice. Taken together, our data indicate that PIASy has a modest effect on cytokine and Wnt signaling, suggesting a redundancy with other members of the family of PIAS proteins.

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Section: Discussionmentioning

confidence: 98%

PIASy-Deficient Mice Display Modest Defects in IFN and Wnt Signaling

Roth

Sustmann

Kieslinger

et al. 2004

The Journal of Immunology

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“…In 1996, we jointly reported the first genetic etiology of MSMD: autosomal recessive complete IFN-γ receptor 1 (IFN-γR1) deficiency (17,18). Over the next 20 y, we and others pursued this forward genetic approach and discovered a group of 17 inborn errors of IFN-γ immunity involving nine genes (19)(20)(21)(22)(23). Some MSMD-causing genes control the production of IFN-γ; others govern its action.…”

Section: Inborn Errors Of Ifn-γ Immunitymentioning

confidence: 99%

Severe infectious diseases of childhood as monogenic inborn errors of immunity

Casanova

2015

Proc. Natl. Acad. Sci. U.S.A.

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This paper reviews the developments that have occurred in the field of human genetics of infectious diseases from the second half of the 20th century onward. In particular, it stresses and explains the importance of the recently described monogenic inborn errors of immunity underlying resistance or susceptibility to specific infections. The monogenic component of the genetic theory provides a plausible explanation for the occurrence of severe infectious diseases during primary infection. Over the last 20 y, increasing numbers of life-threatening infectious diseases striking otherwise healthy children, adolescents, and even young adults have been attributed to single-gene inborn errors of immunity. These studies were inspired by seminal but neglected findings in plant and animal infections. Infectious diseases typically manifest as sporadic traits because human genotypes often display incomplete penetrance (most genetically predisposed individuals remain healthy) and variable expressivity (different infections can be allelic at the same locus). Infectious diseases of childhood, once thought to be archetypal environmental diseases, actually may be among the most genetically determined conditions of mankind. This nascent and testable notion has interesting medical and biological implications.

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“…1A). However, the critical residues for DNA binding and phosphorylation have been identified as Gln-463 and Tyr-701, respectively (5,6). In contrast, GOF mutations clearly accumulate in the CCD and the DBD (Fig.…”

mentioning

confidence: 99%

“…1A). The loss-of-function (LOF) 2 mutations have been associated with the pathogenesis of Mendelian susceptibility to mycobacterial disease, which is a rare syndrome characterized by infections with weakly virulent mycobacteria (5,6). On the other hand, its gain-of-function (GOF) mutations exhibit different immunological defects.…”

mentioning

confidence: 99%

Molecular mechanism and structural basis of gain-of-function of STAT1 caused by pathogenic R274Q mutation

Fujiki

Hijikata

Shirai

et al. 2017

Journal of Biological Chemistry

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Edited by Eric R. FearonGain-of-function (GOF) mutations in the STAT1 gene are critical for the onset of chronic mucocutaneous candidiasis (CMC) disease. However, the molecular basis for the gain of STAT1 function remains largely unclear. Here, we investigated the structural features of STAT1 GOF residues to better understand the impact of these pathogenic mutations. We constructed STAT1 alanine mutants of the ␣3 helix residues of the coiled-coil domain, which are frequently found in CMC pathogenic mutations, and measured their transcriptional activities. Most of the identified GOF residues were located inside the coiled-coil domain stem structure or at the protein surface of the anti-parallel dimer interface. Unlike those, Arg-274 was adjacent to the DNA-binding domain. In addition, Arg-274 was found to functionally interact with Gln-441 in the DNA-binding domain. Because Gln-441 is located at the anti-parallel dimer contact site, Gln-441 reorientation by Arg-274 mutation probably impedes formation of the dimer. Further, the statistical analysis of RNA-seq data with STAT1-deficient epithelial cells and primary T cells from a CMC patient revealed that the R274Q mutation affected gene expression levels of 66 and 76 non-overlapping RefSeq genes, respectively. Because their transcription levels were only slightly modulated by wild-type STAT1, we concluded that the R274Q mutation increased transcriptional activity but did not change dramatically the repertoire of STAT1 targets. Hence, we provide a novel mechanism of STAT1 GOF triggered by a CMC pathogenic mutation.

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Impairment of Mycobacterial But Not Viral Immunity by a Germline Human STAT1 Mutation

Cited by 476 publications

References 22 publications

PIASy-Deficient Mice Display Modest Defects in IFN and Wnt Signaling

PIASy-Deficient Mice Display Modest Defects in IFN and Wnt Signaling

Severe infectious diseases of childhood as monogenic inborn errors of immunity

Molecular mechanism and structural basis of gain-of-function of STAT1 caused by pathogenic R274Q mutation

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