USP4 targets TAK1 to downregulate TNFα-induced NF-κB activation

Fan, Yihui; Ye, Yu; Mao, Renfang; Tan, Xiaojun; Xu, Gufeng; Zhang, H.; Lu, Xiongbin; Fu, Songbin; Yang, Jianhua

doi:10.1038/cdd.2011.11

Cited by 144 publications

(129 citation statements)

References 42 publications

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“…Moreover, a recent study demonstrated that USP4 can deubiquitinate TAK1, a downstream target of TRAF6 (36). While our manuscript was in preparation, another study was published that confirmed the role of USP4 in TRAF6 regulation in vitro (37).…”

Section: Discussionmentioning

confidence: 67%

Ubiquitin-specific Protease 4 Mitigates Toll-like/Interleukin-1 Receptor Signaling and Regulates Innate Immune Activation

Zhou

Zhang

Dam

et al. 2012

Journal of Biological Chemistry

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Background:The TRAF6-mediated Toll-like receptor (TLR)/IL-1 receptor (IL-1R) pathway is essential for innate immune responses and immune homeostasis. Results: USP4 deubiquitinates Lys-63-linked polyubiquitination of TRAF6 and thereby prevents the TLR/IL-1R-induced activation of NF-B and AP-1 transcription factors and subsequent proinflammatory responses. Conclusion: USP4 plays an essential role in the negative regulation of the TLR/IL-1R signaling-mediated innate immune response. Significance: USP4 is an attractive new therapeutic target for modulation of innate immune responses.

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Section: Discussionmentioning

confidence: 67%

Ubiquitin-specific Protease 4 Mitigates Toll-like/Interleukin-1 Receptor Signaling and Regulates Innate Immune Activation

Zhou

Zhang

Dam

et al. 2012

Journal of Biological Chemistry

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“…Knockdown of USP4 in HeLa cells enhanced TNF-ainduced TAK1 polyubiquitylation (70). It is unclear whether Cyld and USP4 can target the K63-linked polyubiquitin chains bound to TAB2 or TAB3.…”

Section: Negative Regulation Of Tak1mentioning

confidence: 99%

“…Other deubiquitinases such as ubiquitin-specific peptidase 4 (USP4) can downregulate TNF-a-induced TAK1 activation (70) by cleavage of K63 polyubiquitin chains conjugated to K158 on TAK1. Knockdown of USP4 in HeLa cells enhanced TNF-ainduced TAK1 polyubiquitylation (70).…”

Section: Negative Regulation Of Tak1mentioning

confidence: 99%

TAK1, more than just innate immunity

et al. 2012

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SummaryTransforming growth factor b-activated kinase 1 (TAK1) is a key regulator of the innate immunity and the proinflammatory signaling pathway. In response to interleukin-1, tumor necrosis factor-a, and toll-like receptor agonists, it mediates the activation of the nuclear factor jB (NF-jB), c-Jun N-terminal kinase (JNK), and p38 pathways. In addition, TAK1 plays a central role in adaptive immunity, in which it mediates signaling from T-and B-cell receptors. This review will focus on recent developments and also examine the regulation of TAK1 in response to a diverse range of other stimuli including DNA damage, transforming growth factor-b, Wnt, osmotic stress, and hypoxia.2012 IUBMB IUBMB Life, 64(10): [825][826][827][828][829][830][831][832][833][834] 2012

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“…Like other USPs, USP4 also mediates the removal and processing of ubiquitin. USP4 binds TRAF2, TRAF6, and TAK1 for deubiquitination and negatively regulates TNFainduced NF-kB activation (9,10). USP4 binds directly to and stabilizes ARF-BP1 via deubiquitination, subsequently promoting ARF-BP1-dependent p53 ubiquitination and degradation (11).…”

Section: Introductionmentioning

confidence: 99%

Ubiquitin-Specific Protease 4-Mediated Deubiquitination and Stabilization of PRL-3 Is Required for Potentiating Colorectal Oncogenesis

Xing

Guo

et al. 2016

Cancer Research

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Ubiquitin specific protease 4 (USP4) is a deubiquitinating enzyme with key roles in the regulation of p53 and TGFb signaling, suggesting its importance in tumorigenesis. However, the mechanisms and regulatory roles of USP4 in cancer, including colorectal cancer, remain largely elusive. Here, we present the first evidence that USP4 regulates the growth, invasion, and metastasis of colorectal cancer. USP4 expression was significantly elevated in colorectal cancer tissues and was significantly associated with tumor size, differentiation, distant metastasis, and poor survival. Knockdown of USP4 diminished colorectal cancer cell growth, colony formation, migration, and invasion in vitro and metastasis in vivo. Importantly, we found that phosphatase of regenerating liver-3 (PRL-3) is indispensable for USP4-mediated oncogenic activity in colorectal cancer.Mechanistically, we observed that USP4 interacted with and stabilized PRL-3 via deubiquitination. This resulted in activation of Akt and reduction of E-cadherin, critical regulators of cancer cell growth and metastasis. Examination of clinical samples confirmed that USP4 expression positively correlates with PRL-3 protein expression, but not mRNA transcript levels. Taken together, our results demonstrate that aberrant expression of USP4 contributes to the development and progression of colorectal cancer and reveal a critical mechanism underlying USP4-mediated oncogenic activity. These observations suggest that the potential of harnessing proteolytic degradation processes for therapeutic manipulation may offer a much-needed new approach for improving colorectal cancer treatment strategies. Cancer Res; 76(1); 83-95. Ó2015 AACR.

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USP4 targets TAK1 to downregulate TNFα-induced NF-κB activation

Cited by 144 publications

References 42 publications

Ubiquitin-specific Protease 4 Mitigates Toll-like/Interleukin-1 Receptor Signaling and Regulates Innate Immune Activation

Ubiquitin-specific Protease 4 Mitigates Toll-like/Interleukin-1 Receptor Signaling and Regulates Innate Immune Activation

TAK1, more than just innate immunity

Ubiquitin-Specific Protease 4-Mediated Deubiquitination and Stabilization of PRL-3 Is Required for Potentiating Colorectal Oncogenesis

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