ATP13A2 facilitates HDAC6 recruitment to lysosome to promote autophagosome-lysosome fusion

• Published in: The Journal of cell biology 2019-01, Vol.218 (1), p.267-284
• Main Authors: Wang, Ruoxi, Tan, Jieqiong, Chen, Tingting, Han, Hailong, Tian, Runyi, Tan, Ya, Wu, Yiming, Cui, Jingyi, Chen, Fang, Li, Jie, Lv, Lu, Guan, Xinjie, Shang, Shuai, Lu, Jiahong, Zhang, Zhuohua
• Format: Article
• Language: English
• Subjects: Acetylation; Aging; Amino Acid Sequence; Anilides - pharmacology; Animals; Autophagosomes - drug effects; Autophagosomes - metabolism; Autophagosomes - ultrastructure; Autophagy; Autophagy - drug effects; Autophagy - genetics; Cellular biology; Cortactin - genetics; Cortactin - metabolism; Disease Models, Animal; Drosophila melanogaster; Enzymes; Fruit flies; Gene Expression Regulation; Genotype & phenotype; Histone Deacetylase 6 - genetics; Histone Deacetylase 6 - metabolism; Histone Deacetylase Inhibitors - pharmacology; Humans; Hydroxamic Acids - pharmacology; Impairment; Leupeptins - pharmacology; Localization; Lysosomal Membrane Proteins - genetics; Lysosomal Membrane Proteins - metabolism; Lysosomes; Lysosomes - drug effects; Lysosomes - metabolism; Lysosomes - ultrastructure; Male; Membrane Fusion - drug effects; Mice; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - pathology; Mitochondria - ultrastructure; Movement disorders; Mutants; Mutation; Neurodegeneration; Neurodegenerative diseases; Parkinson Disease, Secondary - genetics; Parkinson Disease, Secondary - metabolism; Parkinson Disease, Secondary - pathology; Parkinson's disease; Pathogenesis; Phagocytosis; Phenotypes; Proteins; Proton-Translocating ATPases - deficiency; Proton-Translocating ATPases - genetics; Recruitment; Sequence Alignment; Sequence Homology, Amino Acid; Tubulin
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.201804165

Mutations in cause Kufor-Rakeb syndrome, an autosomal recessive form of juvenile-onset atypical Parkinson's disease (PD). Recent work tied to autophagy and other cellular features of neurodegeneration, but how ATP13A2 governs numerous cellular functions in PD pathogenesis is not understood. In this study, the ATP13A2-deficient mouse developed into aging-dependent phenotypes resembling those of autophagy impairment. ATP13A2 deficiency impaired autophagosome-lysosome fusion in cultured cells and in in vitro reconstitution assays. In ATP13A2-deficient cells or or mouse tissues, lysosomal localization and activity of HDAC6 were reduced, with increased acetylation of tubulin and cortactin. Wild-type HDAC6, but not a deacetylase-inactive mutant, restored autophagosome-lysosome fusion, antagonized cortactin hyperacetylation, and promoted lysosomal localization of cortactin in ATP13A2-deficient cells. Mechanistically, ATP13A2 facilitated recruitment of HDAC6 and cortactin to lysosomes. Cortactin overexpression in cultured cells reversed ATP13A2 deficiency-associated impairment of autophagosome-lysosome fusion. PD-causing ATP13A2 mutants failed to rescue autophagosome-lysosome fusion or to promote degradation of protein aggregates and damaged mitochondria. These results suggest that ATP13A2 recruits HDAC6 to lysosomes to deacetylate cortactin and promotes autophagosome-lysosome fusion and autophagy. This study identifies ATP13A2 as an essential molecular component for normal autophagy flux in vivo and implies potential treatments targeting HDAC6-mediated autophagy for PD.