USP4 positively regulates RLR-induced NF-κB activation by targeting TRAF6 for K48-linked deubiquitination and inhibits enterovirus 71 replication

Xu, Chao; Peng, Yang; Zhang, Qin; Xu, Xiaopeng; Kong, Xiang-Min; Shi, Weifeng

doi:10.1038/s41598-018-31734-6

Cited by 22 publications

(12 citation statements)

References 51 publications

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“…Furthermore, RIG-I-MAVS-TRAF6 signaling induces K63-ubiquitination of Beclin-1, a critical step for inducing autophagy (71). Finally, TRAF6 interacts with Ubiquitin-specific protease 4 (USP4) to induce NF-κB activation following RLR-simulation (72). This is achieved via targeting of TRAF6 for K48-linked deubiquitination.…”

Section: The Role Of Trafs In Rig-i-like Receptor Signalingmentioning

confidence: 99%

The Evolving Role of TRAFs in Mediating Inflammatory Responses

et al. 2019

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TRAFs [tumor necrosis factor (TNF) receptor associated factors] are a family of signaling molecules that function downstream of multiple receptor signaling pathways and play a pivotal role in the biology of innate, and adaptive immune cells. Following receptor ligation, TRAFs generally function as adapter proteins to mediate the activation of intracellular signaling cascades. With the exception of TRAF1 that lacks a Ring domain, TRAFs have an E3 ubiquitin ligase activity which also contributes to their ability to activate downstream signaling pathways. TRAF-mediated signaling pathways culminate in the activation of several transcription factors, including nuclear factor-κB (NF-κB), mitogen-activated protein kinases (MAPKs; e.g., ERK-1 and ERK-2, JNK, and p38), and interferon-regulatory factors (IRF; e.g., IRF3 and IRF7). The biological role of TRAFs is largely due to their ability to positively or negatively regulate canonical and non-canonical NF-κB signaling. While TRAF-mediated signaling regulates various immune cell functions, this review is focused on the recent advances in our knowledge regarding the molecular mechanisms through which TRAF proteins regulate, positively and negatively, inflammatory signaling pathways, including Toll–IL-1 receptors, RIG-I like receptors, and Nod-like receptors. The review also offers a perspective on the unanswered questions that need to be addressed to fully understand how TRAFs regulate inflammation.

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Section: The Role Of Trafs In Rig-i-like Receptor Signalingmentioning

confidence: 99%

The Evolving Role of TRAFs in Mediating Inflammatory Responses

et al. 2019

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“…Wu et al (2017) showed that PTEN decreased hepatitis C virus replication and the protein phosphatase activity of PTEN is TRAF6 belongs to the TRAF family and is the key signaling protein in the NF-κB signaling pathways (Liu et al, 2012). TRAF6 could form a homodimer and catalyze K63-linked unbiquitination, which leads to the production of proinflammatory cytokines (Xu, Peng, et al, 2018). In addition, the ubiquitin-specific protease 4 could positively regulate retinoic acid-inducible gene I-like receptorinduced NF-κB activation by targeting TRAF6 for K48-linked deubiquitination and inhibit EV71 replication (Xu, Peng, et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

miR‐545 promoted enterovirus 71 replication via directly targeting phosphatase and tensin homolog and tumor necrosis factor receptor‐associated factor 6

Ying

Long

et al. 2019

Journal Cellular Physiology

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Enterovirus 71 (EV71) is a small, nonenveloped icosahedral RNA virus and is the predominant causative pathogen of hand‐foot‐and‐mouth disease. Recently, microRNAs (miRNAs) are reported to play important roles in the pathogenesis of EV71 replication. This study investigated the role of miR‐545 in the EV71 replication and explored the underlying molecular mechanisms. We showed that miR‐545 was upregulated in the EV71‐infected human embryonic kidney (HEK) 293 cells and rhabdomyosarcoma (RD) cells. Overexpression of miR‐545 promoted the viral replication of EV71 and attenuated the inhibitory effects of EV71 on cell viability in HEK293 and RD cells; while knockdown of miR‐545 significantly suppressed the EV71 replication in these two cell lines. Bioinformatics analysis and luciferase reporter assay showed that miR‐545 directly targeted the 3′untranslated region of phosphatase and tensin homolog (PTEN) and tumor necrosis factor receptor‐associated factor 6 (TRAF6) in HEK293 cells. Furthermore, miR‐545 negatively regulated the messenger RNA (mRNA) and protein expression of PTEN and TRAF6. The mRNA and protein expression of PTEN and TRAF6 was also suppressed by EV71 infection, which was attenuated by miR‐545 knockdown in HEK293 cells. Overexpression of PTEN and TRAF6 both suppressed the EV71 replication in HKE293 cells, and also attenuated the enhanced effects of miR‐545 overexpression on the EV71 replication in HEK293 cells. Collectively, our study for the first time showed that miR‐545 had an enhanced effect on the EV71 replication in HEK293 and RD cells. Further mechanistic results indicated that miR‐545 promoted EV71 replication at least partly via targeting PTEN and TRAF6.

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“…More recently, Xu et al demonstrated that upon enterovirus 71 (EV71) infections, USP4 expression was repressed, whereas the overexpression of USP4 suppressed EV71 replication. Hence, USP4 positively regulates NF-κB signaling by deubiquitinating K48-ubiquitin chains of TRAF6 in EV71 infection [74].…”

Section: Usp4mentioning

confidence: 98%

Importance of Deubiquitination in Macrophage-Mediated Viral Response and Inflammation

Rasaei

Sarodaya

Kim

et al. 2020

IJMS

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Ubiquitination and deubiquitination play a fundamental role in the signaling pathways associated with innate and adaptive immune responses. Macrophages are key sentinels for the host defense, triggering antiviral and inflammatory responses against various invading pathogens. Macrophages recognize the genetic material of these pathogens as pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) through the activation of its pattern recognition receptors (PRRs), initiating the cascade of immune signaling, which leads to the production of pro- and anti-inflammatory cytokines that initiates the appropriate immune response. Macrophage-mediated immune response is highly regulated and tightly controlled by the ubiquitin system since its abnormal activation or dysregulation may result in the severe pathogenesis of numerous inflammatory and autoimmune diseases. Deubiquitinating enzymes (DUBs) play a crucial role in reversing the ubiquitination and controlling the magnitude of the immune response. During infection, pathogens manipulate the host defense system by regulating DUBs to obtain nutrients and increase proliferation. Indeed, the regulation of DUBs by small molecule inhibitors has been proposed as an excellent way to control aberrant activation of immune signaling molecules. This review is focused on the complex role of DUBs in macrophage-mediated immune response, exploring the potential use of DUBs as therapeutic targets in autoimmune and inflammatory diseases by virtue of small molecule DUB inhibitors.

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USP4 positively regulates RLR-induced NF-κB activation by targeting TRAF6 for K48-linked deubiquitination and inhibits enterovirus 71 replication

Cited by 22 publications

References 51 publications

The Evolving Role of TRAFs in Mediating Inflammatory Responses

The Evolving Role of TRAFs in Mediating Inflammatory Responses

miR‐545 promoted enterovirus 71 replication via directly targeting phosphatase and tensin homolog and tumor necrosis factor receptor‐associated factor 6

Importance of Deubiquitination in Macrophage-Mediated Viral Response and Inflammation

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