TRIM21 Ubiquitylates SQSTM1/p62 and Suppresses Protein Sequestration to Regulate Redox Homeostasis

Pan, Jian; Sun, Yu; Jiang, Yaping; Bott, Alex J.; Jaber, Nadia; Dou, Zhixun; Yang, Bin; Chen, Juei‐Suei; Catanzaro, Joseph M.; Du, Can; Ding, Wen–Xing; Diaz‐Meco, María T.; Moscat, Jorge; Ozato, Keiko; Lin, Richard Z.; Zong, Wei‐Xing

doi:10.1016/j.molcel.2016.03.015

Cited by 71 publications

(83 citation statements)

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“…In addition, we identified the functional domains required for their interaction in both TRIM21 and SAMHD1 (Figs 6-8). We found that TRIM21 interacts with SAMHD1 via the PRY and SPRY domains, consistent with the observation that PRYSPRY domains are required for p62 binding [66]. SAMHD1 109-626 could be recognized and degraded by TRIM21, while the amino-terminal 1-547 of SAMHD1 maintained the ability to bind with TRIM21 but could not be degraded by TRIM21.…”

Section: Discussionsupporting

confidence: 88%

TRIM21‐mediated proteasomal degradation of SAMHD1 regulates its antiviral activity

Chen

Wang

et al. 2019

EMBO Reports

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SAMHD1 possesses multiple functions, but whether cellular factors regulate SAMHD1 expression or its function remains not well characterized. Here, by investigating why cultured RD and HEK293T cells show different sensitivity to enterovirus 71 (EV71) infection, we demonstrate that SAMHD1 is a restriction factor for EV71. Importantly, we identify TRIM21, an E3 ubiquitin ligase, as a key regulator of SAMHD1, which specifically interacts and degrades SAMHD1 through the proteasomal pathway. However, TRIM21 has no effect on EV71 replication itself. Moreover, we prove that interferon production stimulated by EV71 infection induces increased TRIM21 and SAMHD1 expression, whereas increasing TRIM21 overrides SAMHD1 inhibition of EV71 in cells and in a neonatal mouse model. TRIM21-mediated degradation of SAMHD1 also affects SAMHD1-dependent restriction of HIV-1 and the regulation of interferon production. We further identify the functional domains in TRIM21 required for SAMHD1 binding and the ubiquitination site K622 in SAMHD1 and show that phosphorylation of SAMHD1 at T592 also blocks EV71 restriction. Our findings illuminate how EV71 overcomes SAMHD1 inhibition via the upregulation of TRIM21.

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Section: Discussionsupporting

confidence: 88%

TRIM21‐mediated proteasomal degradation of SAMHD1 regulates its antiviral activity

Chen

Wang

et al. 2019

EMBO Reports

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“…Second, we found that the inhibitory actions of TRIM17 on autophagy led to p62 accumulation, and p62 has been shown to affect numerous signaling pathways (Katsuragi et al, 2015). A very recent report shows that these signaling events can be affected by the actions of a TRIM upon p62: TRIM21-dependent ubiquitylation of p62 interferes with the ability of p62 to aggregate and sequester Keap1, a negative regulator of cellular responses to oxidative stress (Pan et al, 2016). TRIM17 expression increases the abundance of p62 aggregates, and so would be expected to have an opposing effect to that of TRIM21.…”

Section: Discussionmentioning

confidence: 70%

TRIM17 contributes to autophagy of midbodies while actively sparing other targets from degradation

Mandell

Jain

Kumar

et al. 2016

Journal of Cell Science

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TRIM proteins contribute to selective autophagy, a process whereby cells target specific cargo for autophagic degradation. In a previously reported screen, TRIM17 acted as a prominent inhibitor of bulk autophagy, unlike the majority of TRIMs, which had positive roles. Nevertheless, TRIM17 showed biochemical hallmarks of autophagyinducing TRIMs. To explain this paradox, here, we investigated how TRIM17 inhibits selective autophagic degradation of a subset of targets while promoting degradation of others. We traced the inhibitory function of TRIM17 to its actions on the anti-autophagy protein Mcl-1, which associates with and inactivates Beclin 1. TRIM17 expression stabilized Mcl-1-Beclin-1 complexes. Despite its ability to inhibit certain types of selective autophagy, TRIM17 promoted the removal of midbodies, remnants of the cell division machinery that are known autophagy targets. The selective loss of anti-autophagy Mcl-1 from TRIM17-Beclin-1 complexes at midbodies correlated with the ability of TRIM17 to promote midbody removal. This study further expands the roles of TRIMs in regulating selective autophagy by showing that a single TRIM can, depending upon a target, either positively or negatively regulate autophagy.

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“…Furthermore, phosphorylation of S403 in the UBA domain of p62 by Unc-51 Like Autophagy Activating Kinase 1 (ULK1), Casein kinase II (CKII), or Tank-binding kinase 1 (TBK1), which promotes recruitment of ubiquitylated cargo, plays an important role in the degradation of p62 and its substrates, although whether or not this modification also drives KEAP1 degradation is still uncertain [22–24]. Conversely, ubiquitylation of K7 by tripartite motif family 21 (TRIM21) in the PB1 domain of p62 prevents its oligomerization and interaction with KEAP1, keeping the KEAP1-dependent degradation of NRF2 intact [25]. These studies indicate that the accumulation of p62, as well as enzyme-mediated post-translational modifications of relevant amino acids in its critical domains, are important in mediating the non-canonical activation of NRF2.…”

Section: The Non-canonical Nrf2 Pathwaymentioning

confidence: 99%

Non-Canonical Activation of NRF2: New Insights and Its Relevance to Disease

Dodson

Zhang

2017

Curr Pathobiol Rep

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Purpose of review The goal of this review is to summarize the current knowledge in the field regarding the non-canonical activation of the NRF2 pathway. Specifically, we address what role p62 plays in mediating this pathway, which pathologies have been linked to the p62-dependent activation of NRF2, as well as what therapeutic strategies could be used to treat diseases associated with the non-canonical pathway. Recent findings It has recently been shown that autophagic dysfunction leads to the aggregation or autophagosomal accumulation of p62, which sequesters KEAP1, resulting in prolonged activation of NRF2. The ability of p62 to outcompete NRF2 for KEAP1 binding depends on its abundance, or post-translational modifications to its key domains. Furthermore, the relevance of the p62-dependent activation of NRF2 in disease has been demonstrated in human hepatocellular carcinomas, as well as neurodegenerative diseases. Summary These findings indicate that targeting p62, or the enzymes that modify it, could prove to be an advantageous strategy for treating diseases associated with autophagy dysregulation and prolonged activation of NRF2. Other therapeutic possibilities include restoring proper autophagic function, or directly inhibiting NRF2 or its targets, to restore redox and metabolic homeostasis. Future studies will help further clarify the mechanisms, regulation, and relevance of the non-canonical pathway in driving disease pathogenesis.

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TRIM21 Ubiquitylates SQSTM1/p62 and Suppresses Protein Sequestration to Regulate Redox Homeostasis

Cited by 71 publications

References 0 publications

TRIM21‐mediated proteasomal degradation of SAMHD1 regulates its antiviral activity

TRIM21‐mediated proteasomal degradation of SAMHD1 regulates its antiviral activity

TRIM17 contributes to autophagy of midbodies while actively sparing other targets from degradation

Non-Canonical Activation of NRF2: New Insights and Its Relevance to Disease

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