ATP13A2/PARK9 regulates endo-/lysosomal cargo sorting and proteostasis through a novel PI(3,5)P2-mediated scaffolding function

被引:47
作者
Demirsoy, S. [1 ]
Martin, S. [2 ]
Motamedi, S. [1 ]
van Veen, S. [2 ]
Holemans, T. [2 ]
Van den Haute, C. [3 ]
Jordanova, A. [4 ,5 ]
Baekelandt, V. [3 ]
Vangheluwe, P. [2 ]
Agostinis, P. [1 ]
机构
[1] Univ Leuven KU Leuven, Lab Cell Death Res & Therapy, Dept Cellular & Mol Med, Campus Gasthuisberg,O&N1,Herestraat 49,Box 802, B-3000 Leuven, Belgium
[2] Univ Leuven KU Leuven, Lab Cellular Transport Syst, Dept Cellular & Mol Med, Campus Gasthuisberg,O&N1,Herestraat 49,Box 802, B-3000 Leuven, Belgium
[3] Univ Leuven KU Leuven, Res Grp Neurobiol & Gene Therapy, Dept Neurosci, B-3000 Leuven, Belgium
[4] Univ Antwerp, Mol Neurogen Grp, VIB Ctr Mol Neurol, B-2610 Antwerp, Belgium
[5] Med Univ Sofia, Mol Med Ctr, Dept Med Chem & Biochem, Sofia 1431, Bulgaria
关键词
KUFOR-RAKEB SYNDROME; ALPHA-SYNUCLEIN; PARKINSONS-DISEASE; LYSOSOMAL DYSFUNCTION; QUALITY-CONTROL; MELANOMA; DEFICIENCY; AUTOPHAGY; PARK9; LEADS;
D O I
10.1093/hmg/ddx070
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
ATP13A2 (also called PARK9), is a transmembrane endo-/lysosomal-associated P5 type transport ATPase. Loss-of-function mutations in ATP13A2 result in the Kufor-Rakeb Syndrome (KRS), a form of autosomal Parkinson's disease (PD). In spite of a growing interest in ATP13A2, very little is known about its physiological role in stressed cells. Recent studies suggest that the N-terminal domain of ATP13A2 may hold key regulatory functions, but their nature remains incompletely understood. To this end, we generated a set of melanoma and neuroblastoma cell lines stably overexpressing wild-type (WT), catalytically inactive (D508N) and N-terminal mutants, or shRNA against ATP13A2. We found that under proteotoxic stress conditions, evoked by the proteasome inhibitor Bortezomib, endo-/lysosomal associated full-length ATP13A2 WT, catalytically-inactive or N-terminal fragment mutants, reduced the intracellular accumulation of ubiquitin-conjugated (Ub) proteins, independent of autophagic degradation. In contrast, ATP13A2 silencing increased the intracellular accumulation of Ub-proteins, a pattern also observed in patient-derived fibroblasts harbouring ATP13A2 loss-of function mutations. In treated cells, ATP13A2 evoked endocytic vesicle relocation and increased cargo export through nanovesicles. Expression of an ATP13A2 mutant abrogating PI(3,5)P2 binding or chemical inhibition of the PI(3,5)P2-generating enzyme PIKfyve, compromised vesicular trafficking/nanovesicles export and rescued intracellular accumulation of Ub-proteins in response to proteasomal inhibition. Hence, our study unravels a novel activity-independent scaffolding role of ATP13A2 in trafficking/export of intracellular cargo in response to proteotoxic stress.
引用
收藏
页码:1656 / 1669
页数:14
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