STAT2/IRF9 directs a prolonged ISGF3-like transcriptional response and antiviral activity in the absence of STAT1

Błaszczyk, Katarzyna; Olejnik, Adam; Nowicka, Hanna; Ozgyin, Lilla; Chen, Yi‐Ling; Chmielewski, Stefan; Kostyrko, Kaja; Wesoły, Joanna; Bálint, Bálint László; Lee, Chien‐Kuo; Bluyssen, Hans A.R.

doi:10.1042/bj20140644

Cited by 90 publications

(98 citation statements)

References 45 publications

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“…Previous studies have shown that expression of a fusion protein of STAT2 and IRF9 inhibits the replication of viruses including HCV in the absence of STAT1 (refs 28, 29). It is therefore likely that IFN-α can inhibit HCV replication through the STAT2/IRF9 complex9. Our results also suggest that unlike IFN-α, IFN-λ induces expression of the majority of ISGs and inhibits HCV replication exclusively through a STAT1-dependent pathway.…”

Section: Discussionmentioning

confidence: 55%

See 1 more Smart Citation

STAT1 is essential for the inhibition of hepatitis C virus replication by interferon-λ but not by interferon-α

Yamauchi

Takeuchi

Chihara

et al. 2016

Sci Rep

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Interferon-α (IFN-α) and IFN-λ are structurally distinct cytokines that bind to different receptors, but induce expression of similar sets of genes through Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathways. The difference between IFN-α and IFN-λ signaling remains poorly understood. Here, using the CRISPR/Cas9 system, we examine the role of STAT1 and STAT2 in the inhibition of hepatitis C virus (HCV) replication by IFN-α and IFN-λ. Treatment with IFN-α increases expression of IFN-stimulated genes (ISGs) such as double-stranded RNA-activated protein kinase (PKR) and decreases viral RNA and protein levels in HCV-infected Huh-7.5 human hepatoma cells. These responses are only partially attenuated by knockout of STAT1 but are abolished by knockout of STAT2. In contrast, the inhibition of HCV replication by IFN-λ is abolished by knockout of STAT1 or STAT2. Microarray analysis reveals that IFN-α but not IFN-λ can induce expression of the majority of ISGs in STAT1 knockout cells. These findings suggest that IFN-α can inhibit HCV replication through a STAT2-dependent but STAT1-independent pathway, whereas IFN-λ induces ISG expression and inhibits HCV replication exclusively through a STAT1- and STAT2-dependent pathway.

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Section: Discussionmentioning

confidence: 55%

“…In addition to forming ISGF3, STAT2 can homodimerize and associate with IRF9 to form an ISGF3-like complex58. This complex not only substitutes for ISGF3 but also has its unique target genes9. STAT2 can also heterodimerize with STAT3 or STAT6 (ref.…”

mentioning

confidence: 99%

STAT1 is essential for the inhibition of hepatitis C virus replication by interferon-λ but not by interferon-α

Yamauchi

Takeuchi

Chihara

et al. 2016

Sci Rep

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show abstract

“…Also, it was shown that whereas STAT1 cooperativity is essential for IFN-g response, it is dispensable for IFN-a signaling (30). Very recently, it has been reported that IFN-a activates the STAT2/IRF9 complex that forms an ISGF3-like response without STAT1 and generates an antiviral response in the absence of STAT1 (31). Accordingly, in our report, we show that although SUMO decreased STAT1 phosphorylation in response to IFN-a, it did not alter the formation of ISGF3-like complex and the transcriptional response.…”

Section: Discussionmentioning

confidence: 99%

Small Ubiquitin-like Modifier Alters IFN Response

Maarifi

Maroui

Dutrieux

et al. 2015

The Journal of Immunology

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IFNs orchestrate immune defense through induction of hundreds of genes. Small ubiquitin-like modifier (SUMO) is involved in various cellular functions, but little is known about its role in IFN responses. Prior work identified STAT1 SUMOylation as an important mode of regulation of IFN-γ signaling. In this study, we investigated the roles of SUMO in IFN signaling, gene expression, protein stability, and IFN-induced biological responses. We first show that SUMO overexpression leads to STAT1 SUMOylation and to a decrease in IFN-induced STAT1 phosphorylation. Interestingly, IFNs exert a negative retrocontrol on their own signaling by enhancing STAT1 SUMOylation. Furthermore, we show that expression of each SUMO paralog inhibits IFN-γ–induced transcription without affecting that of IFN-α. Further, we focused on IFN-induced gene products associated to promyelocytic leukemia (PML) nuclear bodies, and we show that neither IFN-α nor IFN-γ could increase PML and Sp100 protein expression because they enhanced their SUMO3 conjugation and subsequent proteasomal degradation. Because it is known that SUMO3 is important for the recruitment of RING finger protein 4, a poly–SUMO-dependent E3 ubiquitin ligase, and that PML acts as a positive regulator of IFN-induced STAT1 phosphorylation, we went on to show that RING finger protein 4 depletion stabilizes PML and is correlated with a positive regulation of IFN signaling. Importantly, inhibition of IFN signaling by SUMO is associated with a reduction of IFN-induced apoptosis, cell growth inhibition, antiviral defense, and chemotaxis. Conversely, inhibition of SUMOylation results in higher IFN-γ–induced STAT1 phosphorylation and biological responses. Altogether, our results uncover a new role for SUMO in the modulation of IFN response.

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“…Although SUMO decreases STAT1 phosphorylation in response to IFN , it does not alter STAT2 phosphorylation, or the formation of an ISGF3 like complex responsible for binding to ISRE and inducing transcriptional and biological responses (7). Accordingly, accumulating evidences support the existence of alternative STAT2 signalling pathways that are independent of STAT1 (30,31). We show here first that in HEK293 SUMO3m cells, STAT1 but not STAT2 activation is lower in response to IFN compared to wt cells.…”

Section: Discussionmentioning

confidence: 74%

Promyelocytic Leukemia Protein (PML) Requirement for Interferon-induced Global Cellular SUMOylation

Maroui

Maarifi

McManus

et al. 2018

Molecular & Cellular Proteomics

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We report that interferon (IFN) α treatment at short and long periods increases the global cellular SUMOylation and requires the presence of the SUMO E3 ligase promyelocytic leukemia protein (PML), the organizer of PML nuclear bodies (NBs). Several PML isoforms (PMLI-PMLVII) derived from a single PML gene by alternative splicing, share the same N-terminal region but differ in their C-terminal sequences. Introducing each of the human PML isoform in PML-negative cells revealed that enhanced SUMOylation in response to IFN is orchestrated by PMLIII and PMLIV. Large-scale proteomics experiments enabled the identification of 558 SUMO sites on 389 proteins, of which 172 sites showed differential regulation upon IFNα stimulation, including K49 from UBC9, the sole SUMO E2 protein. Furthermore, IFNα induces PML-dependent UBC9 transfer to the nuclear matrix where it colocalizes with PML within the NBs and enhances cellular SUMOylation levels. Our results demonstrate that SUMOylated UBC9 and PML are key players for IFN-increased cellular SUMOylation.

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STAT2/IRF9 directs a prolonged ISGF3-like transcriptional response and antiviral activity in the absence of STAT1

Cited by 90 publications

References 45 publications

STAT1 is essential for the inhibition of hepatitis C virus replication by interferon-λ but not by interferon-α

STAT1 is essential for the inhibition of hepatitis C virus replication by interferon-λ but not by interferon-α

Small Ubiquitin-like Modifier Alters IFN Response

Promyelocytic Leukemia Protein (PML) Requirement for Interferon-induced Global Cellular SUMOylation

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