Wakatsuki Shuji, Tokunaga Shinji, Shibata Megumi, Araki Toshiyuki
Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo 187-8502, Japan
Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo 187-8502, Japan.
J Cell Biol. 2017 Feb;216(2):477-493. doi: 10.1083/jcb.201606020. Epub 2017 Jan 4.
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 BECLIN1, 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 BECLIN1 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.
巨自噬是一种分解代谢过程，在此过程中，部分细胞质或细胞器被运送至溶酶体进行降解。新出现的证据表明轴突退变与自噬之间存在病理联系。然而，轴突中自噬的生理功能和诱导机制仍不清楚。我们在此表明，通过激活贝克林1（BECLIN1），糖原合酶激酶3β（GSK3B）介导的BCL2家族成员髓细胞白血病-1（MCL1）磷酸化可诱导轴突自噬和轴突退变。磷酸化的MCL1被F-盒蛋白7（FBXW7）泛素连接酶泛素化，并被蛋白酶体降解，从而释放贝克林1以诱导轴突自噬。轴突自噬有助于退变轴突中局部三磷酸腺苷的产生以及横断轴突上磷脂酰丝氨酸（一种吞噬细胞的“吃我”信号）的暴露，并且是体内吞噬细胞正常募集至轴突碎片所必需的。这些结果表明，GSK3B-MCL1信号传导以调节自噬可能对沃勒变性的成功完成很重要。
