Yap1-Usp14 Axis Inhibits Neuronal Mitophagy During Neonatal Hypoxia–Ischemia Encephalopathy by Regulation of Beclin-1 Ubiquitination in Mouse

Neonatal hypoxic-ischemic encephalopathy (HIE) that results from perinatal cerebral hypoxia–ischemia has become one of the leading causes of acute mortality and chronic disability in infants and children. Despite that neuronal mitophagy and subsequent clearance of damaged neurons exert protective effect, the pathogenesis of HIE and effective treatment strategies for intervention of HIE remain poorly understood. Here, we report that ubiquitin-specific protease 14 (Usp14, a deubiquitinating enzyme) is closely associated with HIE progression by its negative regulation in neuronal mitophagy in mouse. The expression of Usp14 is elevated in both an oxygen–glucose deprivation (OGD) mouse neuronal cell line culture model in vitro and a HIE mouse model in vivo. Mechanistically, OGD treatment activates Hippo signaling that enhances Yap1 phosphorylation levels at Ser-127 but inhibits Yap1 protein level, which potentiates Usp14 transcription and leads to the downregulated ubiquitination at Lys-63 of Beclin-1, a key molecule in autophagy, resulting in the suppressed neuronal mitophagy, subsequent failure in the clearance of damaged neurons, and finally possible dysregulation in brain functions. Thus, our results provide with Usp14 as a novel target and treatment strategy for intervention of HIE, which may help diagnose and treat HIE in clinic.