Computational models of the JAK1/2-STAT1 signaling

Gambin, Anna; Charzyńska, Agata; Ellert-Miklaszewska, Aleksandra; Rybiński, Mikołaj

doi:10.4161/jkst.24672

Cited by 22 publications

(21 citation statements)

References 71 publications

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“…Cytoplasmic STAT‐1 levels were also significantly lower in MAVS aggregate–positive SLE patients than in MAVS aggregate–negative SLE patients and normal controls (Figure A). STAT‐1 activation has been associated with translocation into the nucleus . Decreased cytoplasmic levels of STAT‐1 in MAVS aggregate–positive SLE patients may reflect its activation and translocation into the nucleus.…”

Section: Resultsmentioning

confidence: 99%

Prion‐like Aggregation of Mitochondrial Antiviral Signaling Protein in Lupus Patients Is Associated With Increased Levels of Type I Interferon

Shao

Shu

Zhen

et al. 2016

Arthritis & Rheumatology

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Objective Increased levels of Type I interferon (IFN-I) and IFN-I-regulated genes are found in patients with systemic lupus erythematosus (SLE) and may be central to its pathogenesis. The mitochondrial adaptor protein MAVS is a key regulator of IFN-I that undergoes a dramatic prion-like aggregation and self-propagates the activation signal from viral RNA to amplify downstream IFN production. We wondered if such MAVS aggregates might play a role in the sustained increased production of IFN-I in SLE. Methods Peripheral blood mononuclear cells (PBMCs) were isolated and mitochondrial extracts were prepared. MAVS aggregation was detected with semi-denatured agarose gel electrophoresis (SDD-AGE) and confirmed by immunofluorescence staining. MAVS-associated signaling proteins were analyzed by Western blot. MAVS aggregation-associated gene expression signature was analyzed by microarray. Results Blood cells from 22 of 67 SLE patients were found to have essentially all of their MAVS in a high molecular weight aggregated form. None of six rheumatoid arthritis patients and only three of 33 healthy controls had abnormal MAVS. The MAVS-aggregate positive SLE patients had significantly higher serum levels of IFN-β and significantly increased auto-antibodies against Sm and U1RNP, compared to MAVS-aggregate negative patients. Gene array data revealed a characteristic gene expression pattern in these patients, with altered expression of genes involved in IFN signaling and membrane trafficking. Conclusion Persistent MAVS aggregates may lead to increased IFN-I production and result in unmitigated signals leading to autoimmunity.

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Section: Resultsmentioning

confidence: 99%

Prion‐like Aggregation of Mitochondrial Antiviral Signaling Protein in Lupus Patients Is Associated With Increased Levels of Type I Interferon

Shao

Shu

Zhen

et al. 2016

Arthritis & Rheumatology

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“…Firstly, IFN-γ is a inducer of iNOS which causes damage due to excess NO, and is an important activator of the JAK2/STAT1 pathway [ 45 – 46 ]. Gambin and colleagues reported that IFN-γ produced by macrophages combined with membrane receptors to activate JAK1 and JAK2 which recruited STAT1 [ 47 – 48 ]. Phosphorylated STAT1 was transferred from the cytoplasm into the nucleus to identify the gamma-interferon activation site (GAS) and promote intrinsic apoptosis by inhibiting transcription of anti-apoptotic proteins, Bcl-2 and Bcl-xL, located in the mitochondrial outer membrane [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Pretreatment with Fucoidan from Fucus vesiculosus Protected against ConA-Induced Acute Liver Injury by Inhibiting Both Intrinsic and Extrinsic Apoptosis

Chen

et al. 2016

PLoS ONE

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This study aimed to explore the effects of fucoidan from Fucus vesiculosus on concanavalin A (ConA)-induced acute liver injury in mice. Pretreatment with fucoidan protected liver function indicated by ALT, AST and histopathological changes by suppressing inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ). In addition, intrinsic and extrinsic apoptosis mediated by Bax, Bid, Bcl-2, Bcl-xL and Caspase 3, 8, and 9 were inhibited by fucoidan and the action was associated with the TRADD/TRAF2 and JAK2/STAT1 signal pathways. Our results demonstrated that fucoidan from Fucus vesiculosus alleviated ConA-induced acute liver injury via the inhibition of intrinsic and extrinsic apoptosis mediated by the TRADD/TRAF2 and JAK2/STAT1 pathways which were activated by TNF-α and IFN-γ. These findings could provide a potential powerful therapy for T cell-related hepatitis.

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“…Type-I IFN (IFN-I) activates Janus kinase (JAK)-STAT signaling through the ubiquitously expressed IFN alpha/ beta receptors (IFNAR1 and IFNAR2). Upon IFN-I stimulation, STAT1 is recruited to IFNAR2 and further phosphorylated at the tyrosine 701 site by JAK1 [19][20][21][22][23] . Phosphorylated STAT1 forms the IFN-stimulated gene factor 3 (ISGF3) complex that translocates into the nucleus to induce the expression of hundreds of antiviral IFN-stimulated genes (ISGs) 24 .…”

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confidence: 99%

Regulation of the linear ubiquitination of STAT1 controls antiviral interferon signaling

et al. 2020

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Linear ubiquitination is a critical regulator of inflammatory signaling pathways. However, linearly ubiquitinated substrates and the biological significance of linear ubiquitination is incompletely understood. Here, we show that STAT1 has linear ubiquitination at Lys511 and Lys652 residues in intact cells, which inhibits STAT1 binding to the type-I interferon receptor IFNAR2, thereby restricting STAT1 activation and resulting in type-I interferon signaling homeostasis. Linear ubiquitination of STAT1 is removed rapidly by OTULIN upon type-I interferon stimulation, which facilitates activation of interferon-STAT1 signaling. Furthermore, viruses induce HOIP expression through the NF-κB pathway, which in turn increases linear ubiquitination of STAT1 and thereby inhibits interferon antiviral response. Consequently, HOIL-1L heterozygous mice have active STAT1 signaling and enhanced responses to type-I interferons. These findings demonstrate a linear ubiquitination-mediated switch between homeostasis and activation of type-I interferon signaling, and suggest potential strategies for clinical antiviral therapy.

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Computational models of the JAK1/2-STAT1 signaling

Cited by 22 publications

References 71 publications

Prion‐like Aggregation of Mitochondrial Antiviral Signaling Protein in Lupus Patients Is Associated With Increased Levels of Type I Interferon

Prion‐like Aggregation of Mitochondrial Antiviral Signaling Protein in Lupus Patients Is Associated With Increased Levels of Type I Interferon

Pretreatment with Fucoidan from Fucus vesiculosus Protected against ConA-Induced Acute Liver Injury by Inhibiting Both Intrinsic and Extrinsic Apoptosis

Regulation of the linear ubiquitination of STAT1 controls antiviral interferon signaling

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