STAT6 degradation and ubiquitylated TRIML2 are essential for activation of human oncogenic herpesvirus

Gu, Feng; Wang, Chong; Wei, Fang; Wang, Yuyan; Zhu, Qing; Ding, Lei; Xu, Wenjia; Zhu, Changlian; Cai, Cankun; Zhou, Qian; Yuan, Zhenghong; Robertson, Erle S.; Cai, Qiliang

doi:10.1371/journal.ppat.1007416

Cited by 16 publications

(19 citation statements)

References 41 publications

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“…The results demonstrated that the ubiquitinated STAT6 could be degraded by proteasome and autophagosome–lysosome systems. This finding is consistent with that of the previous reports ( Gu et al, 2018 ) ( Figures 7F,G ).…”

Section: Discussionsupporting

confidence: 94%

“…The mechanisms of the suppression of STAT6 signaling caused by bixin treatment were further explored. According to previous studies, STAT6 can be degraded via ubiquitin-proteasome system and the lysosomal pathway ( Gu et al, 2018 ). Bixin is recognized as an upstream regulator for P62, a major adaptor protein for autophagy degradation of ubiquitinated protein ( Lin et al, 2013 ).…”

Section: Resultsmentioning

confidence: 99%

“…However, the role and the underlying mechanisms of STAT6 in tubular cells in regulating kidney interstitial fibrosis remain unknown. STAT6 can be degraded via ubiquitin–proteasome system and the lysosomal pathway in 293T cells ( Gu et al, 2018 ); in addition, transcriptional activity of STAT6 can be suppressed by the acetylation of STAT6 at Lys383 via the acetyltransferase CBP in macrophages ( Yu et al, 2019 ). SQSTM1(P62) is a key adapter of autophagy, escorting relative ubiquitinated proteins to autolysosomes, and plays a vital role in protein degradation ( Nezis and Stenmark, 2012 ; Katsuragi et al, 2015 ; Aparicio et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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Bixin Protects Against Kidney Interstitial Fibrosis Through Promoting STAT6 Degradation

Yang

Wei

et al. 2020

Front. Cell Dev. Biol.

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Bixin, a natural carotenoid extracted from the seeds of Bixa orellana, has antioxidant and anti-inflammation effects. However, the pharmacological effects and underlying mechanisms of bixin in kidney interstitial fibrosis remain unknown. Partial epithelial-to-mesenchymal transition (EMT) of tubular cells has been linked to renal interstitial fibrosis. Here, we found that in the unilateral ureteral obstruction model, bixin administration could ameliorate kidney interstitial fibrosis. The expression of signal transducer and activator of transcription 6 (STAT6) was dramatically increased in renal tubular cells. Bixin treatment inhibited STAT6 induction. The activation of STAT6 signaling was essential for transforming growth factor β1, fibrotic markers, and EMT-related protein expression in HK2 cells, which was confirmed by using the Stat6–/– mice. Ubiquitination, but not the acetylation level of STAT6, was induced by bixin treatment and promoted the suppression of phosphorylation and stability of STAT6. P62-dependent autophagy might be involved in this process. The study demonstrated that bixin can be exploited therapeutically to alleviate renal interstitial fibrosis by targeting STAT6 signaling deactivation.

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Section: Discussionsupporting

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Bixin Protects Against Kidney Interstitial Fibrosis Through Promoting STAT6 Degradation

Yang

Wei

et al. 2020

Front. Cell Dev. Biol.

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“…2E) (137). Consistent with prolatency functions, STAT6 depletion induced RTA expression and virion production (135,137,138). Notably, IL-4/STAT6 signaling is also reported to induce RTA expression and reactivation of KSHV (139,140), suggesting that full-length STAT6 may be able to activate transcription from the RTA promoter.…”

Section: Stat6mentioning

confidence: 58%

The Dynamic Interface of Viruses with STATs

Harrison

Moseley

2020

J Virol

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Viruses commonly antagonise the antiviral type I interferon response by targeting signal transducers and activators of transcription (STAT) 1 and 2, key mediators of interferon signalling. Other STAT family members mediate signalling by diverse cytokines important to infection, but their relationship with viruses is more complex. Importantly, virus-STAT interaction can be antagonistic or stimulatory depending on diverse viral and cellular factors. While STAT antagonism can suppress immune pathways, many viruses promote activation of specific STATs to support viral gene expression and/or produce cellular conditions conducive to infection. It is also becoming increasingly clear that viruses can hijack non-canonical STAT functions to benefit infection. For a number of viruses, STAT function is dynamically modulated through infection as requirements for replication change. Given the critical role for STATs in infection by diverse viruses, the virus:STAT interface is an attractive target for the development of antivirals and live-attenuated viral vaccines. Here, we review current understanding of the complex and dynamic virus:STAT interface, and discuss how this relationship might be harnessed for medical applications.

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“…After its first isolation from a captive male gibbon [ 3 ], the virus has been recovered from various animal species throughout the world [ 4 – 7 ]. EMCV is often used as a model to study antiviral immune responses, virus-induced myocarditis and insulin dependent diabetes mellitus [ 8 , 9 ]. However, the mechanisms involved in the internalization and entry of the cardioviruses are still not well elucidated [ 2 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Caveolin-1 is involved in encephalomyocarditis virus replication in BHK-21 cells

Liu

et al. 2021

Virol J

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Background Encephalomyocarditis virus, member of Cardiovirus genus within Picornaviridae family, is an important pathogen that infects different domestic and wild animals. However, the molecular mechanism of its entry remains unclear. In this study, we investigated the mechanism of EMCV infectivity in relation to endocytic pathway using BHK-21 cells. Methods The function of numerous cellular key factors implicated in the various endocytic mechanisms were systematically explored using chemical inhibitors. Furthermore, RNA interference (RNAi) as well as the overexpression of dominant protein combined to virus infectivity assays, and confocal microscopy was used to examine EMCV infection in details. Results The results indicated that the EMCV entry into BHK-21 cells depends on caveolin, dynamin, and actin but not clathrin nor macropinocytosis pathways. The effects of overexpression and knockdown of caveolin-1, one components of the caveolae, was examined on EMCV infection. The results showed that EMCV infection was positive correlation with caveolin-1 expression. Confocal microscopy analysis and internalization assay showed that caveolin-1 is required at the early stage of EMCV infection. Conclusions Caveolin-1, dynamin, and actin-dependent endocytosis pathways are necessary for EMCV infection in vitro.

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STAT6 degradation and ubiquitylated TRIML2 are essential for activation of human oncogenic herpesvirus

Cited by 16 publications

References 41 publications

Bixin Protects Against Kidney Interstitial Fibrosis Through Promoting STAT6 Degradation

Bixin Protects Against Kidney Interstitial Fibrosis Through Promoting STAT6 Degradation

The Dynamic Interface of Viruses with STATs

Caveolin-1 is involved in encephalomyocarditis virus replication in BHK-21 cells

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