scholarly journals Structural basis of STAT2 recognition by IRF9 reveals molecular insights into ISGF3 function

2017 ◽  
Author(s):  
Srinivasan Rengachari ◽  
Silvia Groiss ◽  
Juliette Devos ◽  
Elise Caron ◽  
Nathalie Grandvaux ◽  
...  
Keyword(s):  
Cell Fate ◽  
Specific Interaction ◽  
Coiled Coil ◽  
Nuclear Gene ◽  
Type I Interferons ◽  
Structural Basis ◽  
Type I ◽  
Signalling Molecules ◽  
Nuclear Gene Expression ◽  
Selective Interaction

SummaryCytokine signalling is mediated by the activation of distinct sets of structurally homologous JAK and STAT signalling molecules, which control nuclear gene expression and cell fate. A significant expansion in the gene regulatory repertoire controlled by JAK/STAT signalling has arisen by the selective interaction of STATs with IRF transcription factors. Type I interferons (IFN), the major antiviral cytokines, trigger the formation of the ISGF3 complex containing STAT1, STAT2 and IRF9. ISGF3 regulates the expression of IFN–stimulated genes (ISGs). ISGF3 assembly depends on selective interaction between IRF9, through its IRF–association domain (IAD), with the coiled–coil domain (CCD) of STAT2. Here, we report the crystal structures of the IRF9–IAD alone and in a complex with STAT2–CCD. Despite similarity in the overall structure among respective paralogs, the surface features of the IRF9–IAD and STAT2– CCD have diverged to enable specific interaction between these family members, thus enabling ISGF3 formation and expression of ISGs.

scholarly journals Structural basis of STAT2 recognition by IRF9 reveals molecular insights into ISGF3 function

2018 ◽  
Vol 115 (4) ◽  
pp. E601-E609 ◽  
Author(s):  
Srinivasan Rengachari ◽  
Silvia Groiss ◽  
Juliette M. Devos ◽  
Elise Caron ◽  
Nathalie Grandvaux ◽  
...  
Keyword(s):  
Specific Interaction ◽  
Coiled Coil ◽  
Cellular Responses ◽  
Pathogen Resistance ◽  
Structural Basis ◽  
Cytokine Signaling ◽  
Coiled Coil Domain ◽  
Selective Interaction ◽  
Gene Regulatory ◽  
Stat Pathway

Cytokine signaling through the JAK/STAT pathway controls multiple cellular responses including growth, survival, differentiation, and pathogen resistance. An expansion in the gene regulatory repertoire controlled by JAK/STAT signaling occurs through the interaction of STATs with IRF transcription factors to form ISGF3, a complex that contains STAT1, STAT2, and IRF9 and regulates expression of IFN-stimulated genes. ISGF3 function depends on selective interaction between IRF9, through its IRF-association domain (IAD), with the coiled-coil domain (CCD) of STAT2. Here, we report the crystal structures of the IRF9–IAD alone and in a complex with STAT2–CCD. Despite similarity in the overall structure among respective paralogs, the surface features of the IRF9–IAD and STAT2–CCD have diverged to enable specific interaction between these family members. We derive a model for the ISGF3 complex bound to an ISRE DNA element and demonstrate that the observed interface between STAT2 and IRF9 is required for ISGF3 function in cells.

scholarly journals Inactive disease in lupus patients is linked to autoantibodies to type-I interferons that normalize blood IFNα and B cell subsets

2021 ◽  
Author(s):  
Madhvi Menon ◽  
Hannah F. Bradford ◽  
Liis Haljasmagi ◽  
Martti Vanker ◽  
Pärt Peterson ◽  
...  
Keyword(s):  
B Cell ◽  
Lupus Erythematosus ◽  
Type I Interferons ◽  
Inactive Disease ◽  
Type I ◽  
B Cell Differentiation ◽  
Novel Therapy ◽  
Signalling Molecules ◽  
B Cell Subsets

AbstractSystemic Lupus Erythematosus (SLE) is characterized by a prominent increase in expression of type-I interferon (IFN)-regulated genes in 50-75% of patients. Here we investigate the presence of autoantibodies (auto-Abs) against type I IFN in SLE patients and their possible role in controlling disease severity. We report that out of 491 SLE patients, 66 had detectable anti-IFNα-auto-Abs. The presence of neutralizing anti-IFNα-auto-Abs correlates with lower levels of circulating IFNα protein, inhibition of IFN down-stream signalling molecules and gene signatures and with an inactive global disease score. Previously reported B cell frequency abnormalities, found to be involved in SLE pathogenesis, including increased levels of immature, double negative and plasmablast B cell populations were partially normalized in patients with neutralising anti-IFNα-auto-Abs compared to other patient groups. We also show that sera from SLE patients with neutralising anti-IFNα-auto-Abs biases in vitro B cell differentiation towards classical memory phenotype, while sera from patients without anti-IFNα-Abs drives plasmablasts differentiation. Our findings support a role for neutralising anti-IFNα-auto-Abs in controlling SLE pathogenesis and highlight their potential efficacy as novel therapy.

scholarly journals Type I Interferon and the Spectrum of Susceptibility to Viral Infection and Autoimmune Disease: A Shared Genomic Signature

2021 ◽  
Vol 12 ◽  
Author(s):  
Jamie A. Sugrue ◽  
Nollaig M. Bourke ◽  
Cliona O’Farrelly
Keyword(s):  
Autoimmune Disease ◽  
Viral Infection ◽  
Lupus Erythematosus ◽  
Molecular Mechanisms ◽  
Type I Interferons ◽  
Type I ◽  
Nucleotide Polymorphisms ◽  
Genetic Associations ◽  
Signalling Molecules ◽  
Resistance To Viral Infection

Type I interferons (IFN-I) and their cognate receptor, the IFNAR1/2 heterodimer, are critical components of the innate immune system in humans. They have been widely explored in the context of viral infection and autoimmune disease where they play key roles in protection against infection or shaping disease pathogenesis. A false dichotomy has emerged in the study of IFN-I where interferons are thought of as either beneficial or pathogenic. This ‘good or bad’ viewpoint excludes more nuanced interpretations of IFN-I biology - for example, it is known that IFN-I is associated with the development of systemic lupus erythematosus, yet is also protective in the context of infectious diseases and contributes to resistance to viral infection. Studies have suggested that a shared transcriptomic signature underpins both potential resistance to viral infection and susceptibility to autoimmune disease. This seems to be particularly evident in females, who exhibit increased viral resistance and increased susceptibility to autoimmune disease. The molecular mechanisms behind such a signature and the role of sex in its determination have yet to be precisely defined. From a genomic perspective, several single nucleotide polymorphisms (SNPs) in the IFN-I pathway have been associated with both infectious and autoimmune disease. While overlap between infection and autoimmunity has been described in the incidence of these SNPs, it has been overlooked in work and discussion to date. Here, we discuss the possible contributions of IFN-Is to the pathogenesis of infectious and autoimmune diseases. We comment on genetic associations between common SNPs in IFN-I or their signalling molecules that point towards roles in protection against viral infection and susceptibility to autoimmunity and propose that a shared transcriptomic and genomic immunological signature may underlie resistance to viral infection and susceptibility to autoimmunity in humans. We believe that defining shared transcriptomic and genomic immunological signatures underlying resistance to viral infection and autoimmunity in humans will reveal new therapeutic targets and improved vaccine strategies, particularly in females.

Author response for "Type I interferons provide additive signals for murine regulatory B cell induction by Schistosoma mansoni eggs"

2018 ◽  
Author(s):  
Katja Obieglo ◽  
Alice Costain ◽  
Lauren M. Webb ◽  
Arifa Ozir‐Fazalalikhan ◽  
Shelia L. Brown ◽  
...  
Keyword(s):  
B Cell ◽  
Type I Interferons ◽  
Author Response ◽  
Type I ◽  
Regulatory B Cell ◽  
Cell Induction

Type I Interferons promote maintenance and function of follicular T helper cells in vitro

2019 ◽  
Author(s):  
S Ehrlich ◽  
K Wild ◽  
M Smits ◽  
K Zoldan ◽  
M Hofmann ◽  
...  
Keyword(s):  
T Helper Cells ◽  
Type I Interferons ◽  
Type I ◽  
T Helper ◽  
Helper Cells ◽  
Follicular T Helper Cells ◽  
And Function

PLASMACYTOID DENDRITIC CELLS FUNCTION IN HIV INFECTION

2008 ◽  
Vol 31 (4) ◽  
pp. 13
Author(s):  
Martin Hyrcza ◽  
Mario Ostrowski ◽  
Sandy Der
Keyword(s):  
Dendritic Cells ◽  
Influenza Virus ◽  
Hiv Infection ◽  
Gene Transcription ◽  
Sendai Virus ◽  
Plasmacytoid Dendritic Cells ◽  
Type I Interferons ◽  
Interferon Response ◽  
Type I ◽  
Type I Ifn

Plasmacytoid dendritic cells (pDCs) are innate immune cells able to produce large quantities of type I interferons (IFN) when activated. Human immunodeficiency virus (HIV)-infected patients show generalized immune dysfunction characterized in part by chronic interferon response. In this study we investigated the role of dendritic cells inactivating and maintaining this response. Specifically we compared the IFN geneactivity in pDCs in response to several viruses and TLR agonists. We hypothesized that 1) the pattern of IFN gene transcription would differ in pDCs treated with HIV than with other agents, and 2) that pDCs from patients from different stages of disease would respond differently to the stimulations. To test these hypotheses, we obtained pDCs from 15 HIV-infected and uninfected individuals and treated freshly isolated pDCs with either HIV (BAL strain), influenza virus (A/PR/8/34), Sendai virus (Cantell strain), TLR7 agonist(imiquimod), or TLR9 agonist (CpG-ODN) for 6h. Type I IFN gene transcription was monitored by real time qPCRfor IFNA1, A2, A5, A6, A8,A17, B1, and E1, and cytokine levels were assayed by Cytometric Bead Arrays forTNF?, IL6, IL8, IL10, IL1?, and IL12p70. pDC function as determined by these two assays showed no difference between HIV-infected and uninfected patients or between patients with early or chronic infection. Specifically, HIV did notinduce type I IFN gene expression, whereas influenza virus, Sendai virus and imiquimod did. Similarly, HIV failed to induce any cytokine release from pDCs in contrast to influenza virus, Sendai virus and imiquimod, which stimulatedrelease of TNF?, IL6, or IL8. Together these results suggest that the reaction of pDCs to HIV virus is quantitatively different from the response to agents such as virus, Sendai virus, and imiquimod. In addition, pDCs from HIV-infected persons have responses similar to pDCs from uninfected donors, suggesting, that the DC function may not be affected by HIV infection.

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