2. Academic Validation
  3. Lysine crotonylation regulates leucine-deprivation-induced autophagy by a 14-3-3ε-PPM1B axis

Lysine crotonylation regulates leucine-deprivation-induced autophagy by a 14-3-3ε-PPM1B axis

  • Cell Rep. 2022 Dec 20;41(12):111850. doi: 10.1016/j.celrep.2022.111850.
Zilong Zheng 1,  Guokai Yan 1,  Xiuzhi Li 1,  Yuke Fei 1,  Lingling Sun 1,  Haonan Yu 1,  Yaorong Niu 1,  Weihua Gao 1,  Qing Zhong 2,  Xianghua Yan 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, Frontiers Science Center for Animal Breeding and Sustainable Production, College of Animal Sciences and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, China; The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, Hubei 430070, China; Hubei Provincial Engineering Laboratory for Pig Precision Feeding and Feed Safety Technology, Wuhan, Hubei 430070, China.
  • 2 Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: [email protected].
  • 3 State Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, Frontiers Science Center for Animal Breeding and Sustainable Production, College of Animal Sciences and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, China; The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, Hubei 430070, China; Hubei Provincial Engineering Laboratory for Pig Precision Feeding and Feed Safety Technology, Wuhan, Hubei 430070, China. Electronic address: [email protected].
PMID: 36543144 DOI: 10.1016/j.celrep.2022.111850
Abstract

Lysine crotonylation as a protein post-translational modification regulates diverse cellular processes and functions. However, the role of crotonylation in nutrient signaling pathways remains unclear. Here, we find a positive correlation between global crotonylation levels and leucine-deprivation-induced Autophagy. Crotonylome profiling identifies many crotonylated proteins regulated by leucine deprivation. Bioinformatics analysis dominates 14-3-3 proteins in leucine-mediated crotonylome. Expression of 14-3-3ε crotonylation-deficient mutant significantly inhibits leucine-deprivation-induced Autophagy. Molecular dynamics analysis shows that crotonylation increases molecular instability and disrupts the 14-3-3ε amphipathic pocket through which 14-3-3ε interacts with binding partners. Leucine-deprivation-induced 14-3-3ε crotonylation leads to the release of protein Phosphatase 1B (PPM1B) from 14-3-3ε interaction. Active PPM1B dephosphorylates ULK1 and subsequently initiates Autophagy. We further find that 14-3-3ε crotonylation is regulated by HDAC7. Taken together, our findings demonstrate that the 14-3-3ε-PPM1B axis regulated by crotonylation may play a vital role in leucine-deprivation-induced Autophagy.

Keywords

14-3-3ε; CP: Molecular biology; HDAC7; PPM1B; autophagy; crotonylation; leucine deprivation.

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