2. Academic Validation
  3. Destabilization of TP53 by USP10 is essential for neonatal autophagy and survival

Destabilization of TP53 by USP10 is essential for neonatal autophagy and survival

  • Cell Rep. 2022 Oct 4;41(1):111435. doi: 10.1016/j.celrep.2022.111435.
Hongchang Li 1,  Chaonan Li 1,  Wenjing Zhai 1,  Xin Zhang 1,  Lei Li 1,  Bo Wu 1,  Biyue Yu 2,  Pengfei Zhang 1,  Jie Li 3,  Chun-Ping Cui 4,  Lingqiang Zhang 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China.
  • 2 School of Life Sciences, Hebei University, Baoding, Hebei Province 071002, China.
  • 3 Department of Thoracic Surgery, First Medical Center, Chinese PLA General Hospital, Beijing 100853, China. Electronic address: 13801010576@163.com.
  • 4 State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China; School of Life Sciences, Hebei University, Baoding, Hebei Province 071002, China. Electronic address: cui_chunping2000@aliyun.com.
  • 5 State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China. Electronic address: zhanglq@nic.bmi.ac.cn.
PMID: 36198274 DOI: 10.1016/j.celrep.2022.111435
Abstract

Autophagy is essential for the maintenance of energy homeostasis and for survival during the neonatal starvation period. At birth, the trans-placental nutrient supply is suddenly interrupted, and neonates adapt to this adverse circumstance by activating Autophagy. However, the mechanisms underlying the precise regulation of neonatal Autophagy remain undefined. Here, we show that the destabilization of TP53 by the deubiquitylase ubiquitin-specific peptidase 10 (USP10) is essential for neonatal Autophagy and survival. Usp10 deficiency results in decreased E3 Ligase activity of MDM2 and accumulation of cytoplasmic TP53, which interferes with the conjugation of ATG12 and ATG5, the key autophagy-related genes, and ultimately inhibits Autophagy in neonatal mice. Combined deletion of Tp53 and Usp10 recovers the nutrition supply and rescues the death phenotype of Usp10-deficient neonates. These findings reveal a role of the USP10-MDM2-TP53 axis in nutrient homeostasis and neonatal viability and provide insights into the long-perplexing mechanism by which cytoplasmic TP53 inhibits Autophagy.

Keywords

CP: Developmental biology; CP: Molecular biology; TP53; USP10; autophagy; deubiquitination; neonatal survival.

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