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.
摘要：
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,跨胎盘的营养供应突然中断，新生儿通过激活自噬来适应这种不利情况。然而,精确调节新生儿自噬的潜在机制仍不明确.这里,我们表明,去泛素酶泛素特异性肽酶10(USP10)对TP53的去稳定作用对于新生儿自噬和存活至关重要.Usp10缺乏导致MDM2的E3连接酶活性降低和胞质TP53的积累，这干扰了关键自噬相关基因ATG12和ATG5的结合，并最终抑制新生小鼠的自噬。Tp53和Usp10的联合缺失可以恢复营养供应并挽救Usp10缺陷新生儿的死亡表型。这些发现揭示了USP10-MDM2-TP53轴在营养稳态和新生儿生存力中的作用，并提供了对细胞质TP53抑制自噬的长期困惑机制的见解。
