title: 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 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.
authors.affiliation: 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 swaka@ncnp.go.jp taraki@ncnp.go.jp.
authors.forename: Shuji
authors.identifier: 0000-0003-2403-5876
authors.initials: S
authors.lastname: Wakatsuki
authors.affiliation: 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.
authors.forename: Shinji
authors.initials: S
authors.lastname: Tokunaga
authors.affiliation: 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.
authors.forename: Megumi
authors.initials: M
authors.lastname: Shibata
authors.affiliation: 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 swaka@ncnp.go.jp taraki@ncnp.go.jp.
authors.forename: Toshiyuki
authors.identifier: 0000-0003-3625-2042
authors.initials: T
authors.lastname: Araki
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D001369:Axons / Q000201:enzymology* / Q000473:pathology; D000071186:Beclin-1 / Q000378:metabolism; D002478:Cells, Cultured; D044783:F-Box Proteins / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D005727:Ganglia, Spinal / Q000201:enzymology* / Q000473:pathology; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism*; D010586:Phagocytes / Q000378:metabolism; D010587:Phagocytosis; D010718:Phosphatidylserines / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination; D014855:Wallerian Degeneration
chemical_list: D000071186:Beclin-1; C115010:Becn1 protein, mouse; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513272:Fbxw7 protein, mouse; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010718:Phosphatidylserines; D049452:Green Fluorescent Proteins; D000255:Adenosine Triphosphate; D044767:Ubiquitin-Protein Ligases; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D046988:Proteasome Endopeptidase Complex