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.

自噬对于维持能量稳态和新生儿饥饿期间的生存至关重要。出生时，跨-胎盘营养供应突然中断，新生儿通过激活自噬来适应这种不利情况。然而，精确调控新生儿自噬的机制仍未明确。在这里，我们表明去泛素化酶泛素特异性肽酶 10 (USP10) 对 TP53 的不稳定对新生儿自噬和存活至关重要。Usp10 缺乏导致 MDM2 的 E3 连接酶活性降低和细胞质 TP53 的积累，从而干扰关键自噬相关基因 ATG12 和 ATG5 的结合，最终抑制新生小鼠的自噬。Tp53 和 Usp10 的联合缺失恢复了营养供应并挽救了 Usp10 缺陷新生儿的死亡表型。