Ups and downs: The STAT1:STAT3 seesaw of Interferon and gp130 receptor signalling

Regis, Gabriella; Pensa, Sara; Boselli, Daniela; Novelli, Francesco; Poli, Valeria

doi:10.1016/j.semcdb.2008.06.004

Cited by 205 publications

(215 citation statements)

References 161 publications

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“…Although STAT1 and STAT3 activation can be synergistic, some studies show that these proteins may be antagonistic (30). pSTAT1 is not detected in VZVinfected epidermal cells whereas nuclear pSTAT1 is prominent in the uninfected cells (6).…”

Section: Discussionmentioning

confidence: 99%

Signal transducer and activator of transcription 3 (STAT3) and survivin induction by varicella-zoster virus promote replication and skin pathogenesis

Sen¹,

Che²,

Rajamani³

et al. 2011

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

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Varicella-zoster virus (VZV) is a human α-herpesvirus that causes varicella (chickenpox) during primary infection and zoster (shingles) upon reactivation. Like other viruses, VZV must subvert the intrinsic antiviral defenses of differentiated human cells to produce progeny virions. Accordingly, VZV inhibits the activation of the cellular transcription factors IFN regulatory factor 3 (IRF3) and signal transducers and activators of transcription 1 (STAT1), thereby downregulating antiviral factors, including IFNs. Conversely, in this study, we found that VZV triggers STAT3 phosphorylation in cells infected in vitro and in human skin xenografts in SCID mice in vivo and that STAT3 activation induces the anti-apoptotic protein survivin. Small-molecule inhibitors of STAT3 phosphorylation and survivin restrict VZV replication in vitro, and VZV infection of skin xenografts in vivo is markedly impaired by the administration of the phospho-STAT3 inhibitor S3I-201. STAT3 and survivin are required for malignant transformation caused by γ-herpesviruses, such as Kaposi's sarcoma virus. We show that STAT3 activation is also critical for VZV, a nononcogenic herpesvirus, via a survivin-dependent mechanism. Furthermore, STAT3 activation is critical for the life cycle of the virus because VZV skin infection is necessary for viral transmission and persistence in the human population. Therefore, we conclude that takeover of this major cell-signaling pathway is necessary, independent of cell transformation, for herpesvirus pathogenesis and that STAT3 activation and up-regulation of survivin is a common mechanism important for the pathogenesis of lytic as well as tumorigenic herpesviruses.T he life cycle of varicella-zoster virus (VZV) in the human host depends on its tropism for T cells, skin, and neurons within sensory ganglia (1). As shown in the SCID mouse model of VZV pathogenesis, infected human T cells transport the virus to epidermal cells in human skin xenografts and to neural cells in dorsal root ganglia xenografts (2, 3). VZV establishes latency in sensory ganglia; upon reactivation, the virus migrates to the skin via axonal transport to cause zoster.VZV modulates several signaling pathways to replicate efficiently in vitro, and these regulatory effects are especially important in differentiated skin cells infected in vivo. VZV interferes with IFN induction and signaling via inhibition of IFN regulatory factor 3 (IRF3), NFκB, and STAT1 in vitro and in skin (4, 5). However, the pathogenesis of VZV skin infection requires a mechanism to overcome the constitutive IFNα expression by epidermal cells that accounts for the 10-to 21-d interval between VZV transfer into skin and the appearance of lesions at skin surfaces (6). How VZV overcomes this cutaneous IFN barrier and produces skin vesicles is not known.The STATs are ubiquitous transcription factors with many cellular functions and are at the junction of several cytokinesignaling pathways (7,8). Of the seven STAT family proteins, STAT3 exerts widespread effects through transcri...

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Section: Discussionmentioning

confidence: 99%

Signal transducer and activator of transcription 3 (STAT3) and survivin induction by varicella-zoster virus promote replication and skin pathogenesis

Sen¹,

Che²,

Rajamani³

et al. 2011

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

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“…STAT3 phosphorylation status in cells is an indicator of the balance between JAK tyrosine kinase and the phosphatases responsible for STAT3 de-phosphorylation (Regis et al, 2008). Since SENP1-deficient macrophages showed downregulation of JAK2 specifically in response to IFN-γ, we postulated that IFN-γ-induced STAT3 activation might result from the reduction of phosphatasemediated de-phosphorylation in SENP1-deficient macrophages.…”

Section: Senp1 Negatively Regulates Stat3 Activity By Desumoylating Pmentioning

confidence: 96%

“…Among them, STAT1 is activated by IFN-γ (Levy and Darnell, 2002;Ramana et al, 2002;Varinou et al, 2003) during M1 macrophage activation. As a downstream target of cytokine or growth factor receptors, STAT3 always induces expressions of genes (Il10, Tgfb1, Mrc1) associated with M2-like macrophage phenotype to counteract inflammation induced by STAT1 (Hong et al, 2002;Qing and Stark, 2004;Regis et al, 2008). Interestingly, STAT1 and STAT3 activation can be regulated reciprocally (Regis et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…As a downstream target of cytokine or growth factor receptors, STAT3 always induces expressions of genes (Il10, Tgfb1, Mrc1) associated with M2-like macrophage phenotype to counteract inflammation induced by STAT1 (Hong et al, 2002;Qing and Stark, 2004;Regis et al, 2008). Interestingly, STAT1 and STAT3 activation can be regulated reciprocally (Regis et al, 2008). For example, IFN-γ activates macrophages through STAT3 signaling in Stat1−/− cells.…”

Section: Introductionmentioning

confidence: 99%

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SENP1 regulates IFN-γ−STAT1 signaling through STAT3−SOCS3 negative feedback loop

Zuo

Cai

et al. 2016

Journal of Molecular Cell Biology

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Interferon-γ (IFN-γ) triggers macrophage for inflammation response by activating the intracellular JAK−STAT1 signaling. Suppressor of cytokine signaling 1 (SOCS1) and protein tyrosine phosphatases can negatively modulate IFN-γ signaling. Here, we identify a novel negative feedback loop mediated by STAT3−SOCS3, which is tightly controlled by SENP1 via de-SUMOylation of protein tyrosine phosphatase 1B (PTP1B), in IFN-γ signaling. SENP1-deficient macrophages show defects in IFN-γ signaling and M1 macrophage activation. PTP1B in SENP1-deficient macrophages is highly SUMOylated, which reduces PTP1B-induced de-phosphorylation of STAT3. Activated STAT3 then suppresses STAT1 activation via SOCS3 induction in SENP1-deficient macrophages. Accordingly, SENP1-deficient macrophages show reduced ability to resist Listeria monocytogenes infection. These results reveal a crucial role of SENP1-controlled STAT1 and STAT3 balance in macrophage polarization.

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“…109 The balance between STAT1 and STAT3 is dysregulated in LAM, and is thought to control the fate of neoplastic cells. 120 mTOR also activates NF-kB, a pro-proliferative transcription factor implicated in the pathogenesis of cancer. 121 Others demonstrated a physical association between mTOR and IKKa, the IkB kinase required for NF-kB translocation to the nucleus.…”

Section: Gene Transcriptionmentioning

confidence: 99%

mTOR Signaling in Lymphangioleiomyomatosis

Kristof

2010

Lymphatic Research and Biology

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The protein mammalian target of rapamycin (mTOR) plays a central role in cell growth and proliferation. Excessive mTOR activity is a prominent feature of many neoplasms and hamartoma syndromes, including lymphangioleiomyomatosis (LAM), a destructive lung disease that causes progressive respiratory failure in women. Although pharmacological inhibitors of mTOR should directly target the pathogenesis of these disorders, their clinical efficacy has been suboptimal. Recent scientific findings reviewed here have greatly improved our understanding of mTOR signaling mechanisms, provided new insights into the control of cell growth and proliferation, and facilitated the development of new therapeutic approaches in LAM, as well as other neoplastic disorders that exhibit excessive mTOR activity.

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Ups and downs: The STAT1:STAT3 seesaw of Interferon and gp130 receptor signalling

Cited by 205 publications

References 161 publications

Signal transducer and activator of transcription 3 (STAT3) and survivin induction by varicella-zoster virus promote replication and skin pathogenesis

Signal transducer and activator of transcription 3 (STAT3) and survivin induction by varicella-zoster virus promote replication and skin pathogenesis

SENP1 regulates IFN-γ−STAT1 signaling through STAT3−SOCS3 negative feedback loop

mTOR Signaling in Lymphangioleiomyomatosis

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