TRIM21 Ubiquitylates SQSTM1/p62 and Suppresses Protein Sequestration to Regulate Redox Homeostasis.
TRIM21 Ubiquitylates SQSTM1/p62 and Suppresses Protein Sequestration to Regulate Redox Homeostasis.
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DOI：
10.1016/j.molcel.2016.02.007
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发表时间：
2016-03-03
期刊：
影响因子：
16
通讯作者：
Zong WX
中科院分区：
文献类型：
--
作者：
Pan JA;Sun Y;Jiang YP;Bott AJ;Jaber N;Dou Z;Yang B;Chen JS;Catanzaro JM;Du C;Ding WX;Diaz-Meco MT;Moscat J;Ozato K;Lin RZ;Zong WX
TRIM 21是一种含有环指结构域的泛素E3连接酶，其表达在自身免疫性疾病中升高。虽然TRIM 21在病原体感染期间的免疫激活中起重要作用，但对其固有的细胞功能知之甚少。在这里，我们表明TRIM 21通过直接与SQSTM 1/p62相互作用并通过K63-连接在赖氨酸（K）7处泛素化p62在氧化还原调节中起重要作用。由于p62寡聚化和螯合包含物中的客户蛋白，TRIM 21介导的p62泛素化消除了p62寡聚化和螯合蛋白，包括抗氧化反应的负调节因子Keap 1。TRIM 21缺陷细胞显示出增强的抗氧化反应和减少的细胞死亡，以响应氧化应激。小鼠TRIM 21基因切除可保护小鼠免受砷诱导的肝损伤和压力超负荷心脏损伤引起的氧化损伤。因此，TRIM 21在p62调节的氧化还原稳态中起重要作用，并且可能是治疗由氧化损伤引起的病理状况的可行靶标。
TRIM21 is a RING finger domain-containing ubiquitin E3 ligase whose expression is elevated in autoimmune disease. While TRIM21 plays an important role in immune activation during pathogen infection, little is known about its inherent cellular function. Here we show that TRIM21 plays an essential role in redox regulation by directly interacting with SQSTM1/p62 and ubiquitylating p62 at lysine(K)7 via K63-linkage. As p62 oligomerizes and sequesters client proteins in inclusions, the TRIM21-mediated p62 ubiquitylation abrogates p62 oligomerization and sequestration of proteins including Keap1, a negative regulator of antioxidant response. TRIM21-deficient cells display an enhanced antioxidant response and reduced cell death in response to oxidative stress. Genetic ablation of TRIM21 in mice confers protection from oxidative damages caused by arsenic-induced liver insult and pressure overload heart injury. Therefore, TRIM21 plays an essential role in p62-regulated redox homeostasis and may be a viable target for treating pathological conditions resulting from oxidative damage.