NEDD4 promotes reactive astrogliosis by enhancing K63-linked ubiquitination and inhibiting chaperone-mediated autophagy degradation of YAP1.

Following spinal cord injury (SCI), the transcriptional regulator yes-associated protein 1 (YAP1) is upregulated and accumulates in the nuclei of astrocytes, where it promotes reactive astrogliosis-a process that critically influences wound healing and neurological function recovery. However, the mechanisms regulating YAP1 in reactive astrocytes after SCI remain largely unclear. This study, we identify the E3 ubiquitin ligase NEDD4 as a critical regulator of astrocyte reactive proliferation. NEDD4 enhances astrogliosis by suppressing YAP1 degradation. Conditional deletion of Nedd4 in astrocytes markedly attenuates reactive astrogliosis in vivo, and results in heightened inflammation, exacerbated neuronal injury, and impaired functional recovery following SCI. Importantly, YAP1 overexpression is sufficient to reverse the pathological and functional consequences of Nedd4 deficiency. Mechanistically, NEDD4 interacts with YAP1 and mediates K63-linked ubiquitination at lysine 254, thereby preventing its degradation via the chaperone-mediated autophagy (CMA) pathway involving HSC70. Furthermore, we demonstrate that the ROS-FOXM1 signaling cascade drives NEDD4 expression, thereby stabilizing YAP1 and promoting astrocyte proliferation. In summary, our findings underscore the pivotal role of the ROS-FOXM1-NEDD4-YAP1 signaling cascade in controlling astrocytic activation and tissue regeneration post-SCI, positioning NEDD4 as a viable target to regulate astrogliosis and facilitate neurological restoration after SCI.