A molecular mechanism to regulate lysosome motility for lysosome positioning and tubulation

被引：277

作者：

Li, Xinran ^{[1
]}

Rydzewski, Nicholas ^{[1
]}

Hider, Ahmad ^{[1
]}

Zhang, Xiaoli ^{[1
]}

Yang, Junsheng ^{[2
]}

Wang, Wuyang ^{[1
]}

Gao, Qiong ^{[1
]}

Cheng, Xiping ^{[1
]}

Xu, Haoxing ^{[1
]}

机构：

[1] Univ Michigan, Dept Mol Cellular & Dev Biol, 3089 Nat Sci Bldg Kraus,830 North Univ, Ann Arbor, MI 48109 USA

[2] Zhejiang Univ Technol, Coll Pharmaceut Sci, Collaborat Innovat Ctr Yangtze River Delta Reg Gr, Hangzhou 310014, Zhejiang, Peoples R China

来源：

NATURE CELL BIOLOGY | 2016年 / 18卷 / 04期

关键词：

CA2+ CHANNEL; PROTEIN RILP; TRP CHANNEL; MUCOLIPIDOSIS; TRANSPORT; CHOLESTEROL; MEMBRANE; RAB7; KINESIN; TRAFFICKING;

D O I：

10.1038/ncb3324

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

To mediate the degradation of biomacromolecules, lysosomes must traffic towards cargo-carrying vesicles for subsequent membrane fusion or fission. Mutations of the lysosomal Ca2+ channel TRPML1 cause lysosomal storage disease (LSD) characterized by disordered lysosomal membrane trafficking in cells. Here we show that TRPML1 activity is required to promote Ca2+-dependent centripetal movement of lysosomes towards the perinuclear region (where autophagosomes accumulate) following autophagy induction. ALG-2, an EF-hand-containing protein, serves as a lysosomal Ca2+ sensor that associates physically with the minus-end-directed dynactin-dynein motor, while PtdIns(3,5) P-2, a lysosome-localized phosphoinositide, acts upstream of TRPML1. Furthermore, the PtdIns(3,5) P-2-TRPML1-ALG-2-dynein signalling is necessary for lysosome tubulation and reformation. In contrast, the TRPML1 pathway is not required for the perinuclear accumulation of lysosomes observed in many LSDs, which is instead likely to be caused by secondary cholesterol accumulation that constitutively activates Rab7-RILP-dependent retrograde transport. Ca2+ release from lysosomes thus provides an on-demand mechanism regulating lysosome motility, positioning and tubulation.

引用

页码：404 / +

页数：26

共 70 条

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