Phase separation of Nur77 mediates celastrol-induced mitophagy by promoting the liquidity of p62/SQSTM1 condensates

Shuang-zhou Peng, Xiao-hui Chen, Si-jie Chen, Jie Zhang, Chuan-ying Wang, Wei-rong Liu, Duo Zhang, Ying Su and Xiao-kun Zhang ()
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Shuang-zhou Peng: Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University
Xiao-hui Chen: Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University
Si-jie Chen: Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University
Jie Zhang: Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University
Chuan-ying Wang: Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University
Wei-rong Liu: Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University
Duo Zhang: Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University
Ying Su: Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University
Xiao-kun Zhang: Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract Liquid-liquid phase separation promotes the formation of membraneless condensates that mediate diverse cellular functions, including autophagy of misfolded proteins. However, how phase separation participates in autophagy of dysfunctional mitochondria (mitophagy) remains obscure. We previously discovered that nuclear receptor Nur77 (also called TR3, NGFI-B, or NR4A1) translocates from the nucleus to mitochondria to mediate celastrol-induced mitophagy through interaction with p62/SQSTM1. Here, we show that the ubiquitinated mitochondrial Nur77 forms membraneless condensates capable of sequestrating damaged mitochondria by interacting with the UBA domain of p62/SQSTM1. However, tethering clustered mitochondria to the autophagy machinery requires an additional interaction mediated by the N-terminal intrinsically disordered region (IDR) of Nur77 and the N-terminal PB1 domain of p62/SQSTM1, which confers Nur77-p62/SQSTM1 condensates with the magnitude and liquidity. Our results demonstrate how composite multivalent interaction between Nur77 and p62/SQSTM1 coordinates to sequester damaged mitochondria and to connect targeted cargo mitochondria for autophagy, providing mechanistic insight into mitophagy.

Date: 2021
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DOI: 10.1038/s41467-021-26295-8

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