GSK3B-mediated phosphorylation of MCL1 regulates axonal autophagy to promote Wallerian degeneration

Abstract

Macroautophagy is a catabolic process, in which portions of cytoplasm or organelles are delivered to lysosomes for degradation. Emerging evidence has indicated a pathological connection between axonal degeneration and autophagy. However, the physiological function and induction mechanism of autophagy in axons remain elusive. We herein show that, through activation of BEC LIN1, glycogen synthase kinase 3B (GSK3B)-mediated phosphorylation of BCL2 family member MCL1 induces axonal autophagy and axonal degeneration. Phosphorylated MCL1 is ubiquitinated by the FBXW7 ubiquitin ligase and degraded by the proteasome, thereby releasing BEC LIN1 to induce axonal autophagy. Axonal autophagy contributes to local adenosine triphosphate production in degenerating axons and the exposure of phosphatidylserine-an "eat-me" signal for phagocytes-on transected axons and is required for normal recruitment of phagocytes to axonal debris in vivo. These results suggest that GSK3B-MCL1 signaling to regulate autophagy might be important for the successful completion of Wallerian degeneration.