Role of Ubiquitylation in Controlling Suppressor of Cytokine Signalling 3 (SOCS3) Function and Expression

Williams, Jamie J.L.; Munro, Kirsten Margaret Anderson; Palmer, Timothy M.

doi:10.3390/cells3020546

Cited by 36 publications

(34 citation statements)

References 72 publications

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“…In addition, Socs1 and Socs3 are known to function as part of a multi-subunit E3 ubiquitin ligase complex, and mark target proteins for proteasomal degradation. 39 , 40 Using immunoprecipitation assays, we found that both Socs1 and Socs3 could integrate Traf6 to form a complex. Moreover, ubiquitination of Traf6 was enhanced in cells overexpressing Socs1 or Socs3, resulting in the accelerated degradation of Traf6.…”

Section: Discussionmentioning

confidence: 96%

Socs1 and Socs3 degrades Traf6 via polyubiquitination in LPS-induced acute necrotizing pancreatitis

et al. 2015

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Mechanisms involved in inflammatory development during acute pancreatitis (AP) are largely vague, especially in the transformation of acute edematous pancreatitis (AEP) into acute necrotizing pancreatitis (ANP). This current study aims to investigate the functions of Traf6 in different AP models in vitro and in vivo, and to identify the possible regulatory mechanism in the progression of inflammation from mild to severe. Our data revealed that the level of Traf6 expression was significantly increased in the mild AP induced by caerulein, and the upregulation of Traf6 played a protective role in acinar cells against caerulein-induced apoptosis. In contrast, only Traf6 protein but not mRNA was downregulated in the severe ANP induced by combination treatment of caerulein and LPS. Mechanistic studies showed that LPS upregulated the levels of Socs1 and Socs3 expressions in acinar cells, Socs1 and Socs3 interacted Traf6 directly and degraded Traf6 protein via polyubiquitination, thereby counteracted the protective function of Traf6. In vivo study further showed that combination treatment of caerulein and LPS failed to induce an ANP model in the TLR4 knockout mice, and the level of Traf6 expression in the pancreatic tissues remained the same as that from the acute edematous pancreatitis (AEP) mouse. Taken together, our study reveals that Traf6 functioned as a protective factor in the progression of AP, and LPS-induced Socs1 and Socs3 exacerbate mild AP to severe AP, which provides evidence for developing a new therapeutic target to combat AP.

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Section: Discussionmentioning

confidence: 96%

Socs1 and Socs3 degrades Traf6 via polyubiquitination in LPS-induced acute necrotizing pancreatitis

et al. 2015

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“…The ubiquitination reaction consists of the covalent attachment of ubiquitin (an 8-kDa polypeptide) to lysine residues in target proteins4041. Additionally, small ubiquitin-like modifier (SUMO) proteins 1, 2 and 3 can be covalently conjugated to specific lysine residues in target proteins by a process termed SUMOylation4243.…”

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confidence: 99%

Suppression of Rac1 Signaling by Influenza A Virus NS1 Facilitates Viral Replication

Jiang

Sheng

et al. 2016

Sci Rep

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Influenza A virus (IAV) is a major human pathogen with the potential to become pandemic. IAV contains only eight RNA segments; thus, the virus must fully exploit the host cellular machinery to facilitate its own replication. In an effort to comprehensively characterize the host machinery taken over by IAV in mammalian cells, we generated stable A549 cell lines with over-expression of the viral non-structural protein (NS1) to investigate the potential host factors that might be modulated by the NS1 protein. We found that the viral NS1 protein directly interacted with cellular Rac1 and facilitated viral replication. Further research revealed that NS1 down-regulated Rac1 activity via post-translational modifications. Therefore, our results demonstrated that IAV blocked Rac1-mediated host cell signal transduction through the NS1 protein to facilitate its own replication. Our findings provide a novel insight into the mechanism of IAV replication and indicate new avenues for the development of potential therapeutic targets.

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“…Following their induction, STAT expression levels decline within 20-140 minutes additionally via ubiquitination. 26 SOCS3 is the predominant regulator. 27 Thus, activated STAT3, like PtdIns 3,4,5-P 3 , serves as a sensor which regulates its own activation.…”

Section: Discussionmentioning

confidence: 99%

RTK signaling requires C3ar1/C5ar1 and IL‐6R joint signaling to repress dominant PTEN, SOCS1/3 and PHLPP restraint

et al. 2019

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How receptor tyrosine kinase (RTK) growth signaling is controlled physiologically is incompletely understood. We have previously provided evidence that the survival and mitotic activities of vascular endothelial cell growth factor receptor-2 (VEGFR2) signaling are dependent on C3a/C5a receptor (C3ar1/C5ar1) and IL-6 receptor (IL-6R)-gp130 joint signaling in a physically interactive platform. Herein, we document that the platelet derived and epidermal growth factor receptors (PDGFR and EGFR) are regulated by the same interconnection and clarify the mechanism underlying the dependence. We show that the joint signaling is required to overcome dominant restraint on RTK function by the combined repression of tonically activated PHLPP, SOCS1/SOCS3, and CK2/Fyn dependent PTEN. Signaling studies showed that augmented PI-3Kɣ activation is the process that overcomes the multilevel growth restraint. Live-cell flow cytometry and single-particle tracking indicated that blockade of C3ar1/C5ar1 or IL-6R signaling suppresses RTK growth factor binding and RTK complex formation. C3ar1/C5ar1 blockade abrogated growth signaling of four additional RTKs. Active relief of dominant growth repression via joint C3ar1/C5ar1 and IL-6R joint signaling thus enables RTK mitotic/survival signaling. K E Y W O R D SIL-6 receptor, local complement, VEGFR2 signaling 2106 |

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Role of Ubiquitylation in Controlling Suppressor of Cytokine Signalling 3 (SOCS3) Function and Expression

Cited by 36 publications

References 72 publications

Socs1 and Socs3 degrades Traf6 via polyubiquitination in LPS-induced acute necrotizing pancreatitis

Socs1 and Socs3 degrades Traf6 via polyubiquitination in LPS-induced acute necrotizing pancreatitis

Suppression of Rac1 Signaling by Influenza A Virus NS1 Facilitates Viral Replication

RTK signaling requires C3ar1/C5ar1 and IL‐6R joint signaling to repress dominant PTEN, SOCS1/3 and PHLPP restraint

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