p62/SQSTM1 Is a Target Gene for Transcription Factor NRF2 and Creates a Positive Feedback Loop by Inducing Antioxidant Response Element-driven Gene Transcription
p62/SQSTM1 Is a Target Gene for Transcription Factor NRF2 and Creates a Positive Feedback Loop by Inducing Antioxidant Response Element-driven Gene Transcription
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DOI：
10.1074/jbc.m110.118976
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发表时间：
2010-07-16
影响因子：
4.8
通讯作者：
Johansen, Terje
中科院分区：
文献类型：
--
作者：
Jain, Ashish;Lamark, Trond;Johansen, Terje
P62/SQSTM1（Secestosom 1）蛋白充当泛素化靶标自噬降解的货物受体，由各种应激源上调。通过NF-E2相关因子2（NRF2）介导了p62基因的诱导，同时，p62蛋白有助于NRF2的激活，但迄今为止所涉及的机制尚不清楚。本文中，我们在p62启动子中绘制了抗氧化剂反应元件（IS），该抗氧化剂通过NRF2负责氧化应激的诱导。染色质免疫沉淀和凝胶迁移率分析验证了NRF2与体内和体外的顺式元素结合。此外，p62通过指定Keap1相互作用区域（KIR）的主题直接登上Kelch样ECH相关蛋白1（KEAP1）的Kelch-Repeat域（KEAP1），从而阻止了Keap1和NRF2之间的结合，从而导致了泛素化和泛素化和脱落的结合。转录因子。 p62中的KIR基序位于LC3相互作用区域（LIR）的C末端，类似于NRF2与KEAP1相互作用的ETGE基序。 p62稳定NRF2需要KIR，p62对Keap1的抑制是从细胞内的细胞质位置发生的。 LC3和KEAP1不能同时参与LIR和KIR图案，但是由于p62是聚合物，Keap1和p62之间的相互作用会导致KEAP1在p62身体中的积累，随后是Keap1的自噬降解。我们的数据解释了p62如何通过创建正反馈回路来响应氧化应激而响应NRF2靶基因的激活。
The p62/SQSTM1 (sequestosome 1) protein, which acts as a cargo receptor for autophagic degradation of ubiquitinated targets, is up-regulated by various stressors. Induction of the p62 gene by oxidative stress is mediated by NF-E2-related factor 2 (NRF2) and, at the same time, p62 protein contributes to the activation of NRF2, but hitherto the mechanisms involved were not known. Herein, we have mapped an antioxidant response element (ARE) in the p62 promoter that is responsible for its induction by oxidative stress via NRF2. Chromatin immunoprecipitation and gel mobility-shift assays verified that NRF2 binds to this cis-element in vivo and in vitro. Also, p62 docks directly onto the Kelch-repeat domain of Kelch-like ECH-associated protein 1 (KEAP1), via a motif designated the KEAP1 interacting region (KIR), thereby blocking binding between KEAP1 and NRF2 that leads to ubiquitylation and degradation of the transcription factor. The KIR motif in p62 is located immediately C-terminal to the LC3-interacting region (LIR) and resembles the ETGE motif utilized by NRF2 for its interaction with KEAP1. KIR is required for p62 to stabilize NRF2, and inhibition of KEAP1 by p62 occurs from a cytoplasmic location within the cell. The LIR and KIR motifs cannot be engaged simultaneously by LC3 and KEAP1, but because p62 is polymeric the interaction between KEAP1 and p62 leads to accumulation of KEAP1 in p62 bodies, which is followed by autophagic degradation of KEAP1. Our data explain how p62 contributes to activation of NRF2 target genes in response to oxidative stress through creating a positive feedback loop.