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ATP13A2 facilitates HDAC6 recruitment to lysosome to promote autophagosome–lysosome fusion
Ruoxi Wang1; Jieqiong Tan1; Tingting Chen1; Hailong Han1; Runyi Tian1; Ya Tan1; Yiming Wu1; Jingyi Cu1; Fang Chen1; Jie Li1; Lu Lv1; Xinjie Guan1; Shuai Shang1; Jiahong Lu2; Zhuohua Zhang1,3
2019-01
Source PublicationJOURNAL OF CELL BIOLOGY
ISSN0021-9525
Volume218Issue:1Pages:267-284
Abstract

Mutations in ATP13A2 cause Kufor-Rakeb syndrome, an autosomal recessive form of juvenile-onset atypical Parkinson's disease (PD). Recent work tied ATP13A2 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 Drosophila melanogaster 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.

DOI10.1083/jcb.201804165
Indexed BySCI
Language英语
WOS Research AreaCell Biology
WOS SubjectCell Biology
WOS IDWOS:000455041500023
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Cited Times [WOS]:11   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Affiliation1.Institute of Molecular Precision Medicine, Xiangya Hospital and Center for Medical Genetics, Central South University, Changsha, Hunan, China
2.State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau
3.Department of Neurosciences, School of Medicine, University of South China, Hengyang, Hunan, China
Recommended Citation
GB/T 7714
Ruoxi Wang,Jieqiong Tan,Tingting Chen,et al. ATP13A2 facilitates HDAC6 recruitment to lysosome to promote autophagosome–lysosome fusion[J]. JOURNAL OF CELL BIOLOGY,2019,218(1):267-284.
APA Ruoxi Wang.,Jieqiong Tan.,Tingting Chen.,Hailong Han.,Runyi Tian.,...&Zhuohua Zhang.(2019).ATP13A2 facilitates HDAC6 recruitment to lysosome to promote autophagosome–lysosome fusion.JOURNAL OF CELL BIOLOGY,218(1),267-284.
MLA Ruoxi Wang,et al."ATP13A2 facilitates HDAC6 recruitment to lysosome to promote autophagosome–lysosome fusion".JOURNAL OF CELL BIOLOGY 218.1(2019):267-284.
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