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Dev Cell. 2014 Aug 25;30(4):378-93. doi: 10.1016/j.devcel.2014.07.005.

Rab8a-AS160-MSS4 regulatory circuit controls lipid droplet fusion and growth.

Author information

1
MOE Key Laboratory of Bioinformatics and Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
2
MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Pukou District, Nanjing 210061, China.
3
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney NSW 2052, Australia.
4
Cell Biology Core Facility and Proteomics Facility, School of Life Sciences, Tsinghua University, Beijing 100084, China.
5
Department of Pathology, The Fourth Military Medical University, Xi'an 710032, China.
6
Department of Biological Sciences and Centre for Bioimaging Sciences, National University of Singapore, Singapore 117543, Singapore.
7
MOE Key Laboratory of Bioinformatics and Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China. Electronic address: li-peng@mail.tsinghua.edu.cn.

Abstract

Rab GTPases, by targeting to specific membrane compartments, play essential roles in membrane trafficking. Lipid droplets (LDs) are dynamic subcellular organelles whose growth is closely linked to obesity and hepatic steatosis. Fsp27 is shown to be required for LD fusion and growth by enriching at LD-LD contact sites. Here, we identify Rab8a as a direct interactor and regulator of Fsp27 in mediating LD fusion in adipocytes. Knockdown of Rab8a in the livers of ob/ob mice results in the accumulation of smaller LDs and lower hepatic lipid levels. Surprisingly, it is the GDP-bound form of Rab8a that exhibits fusion-promoting activity. We further discover AS160 as the GTPase activating protein (GAP) for Rab8a, which forms a ternary complex with Fsp27 and Rab8a to positively regulate LD fusion. MSS4 antagonizes Fsp27-mediated LD fusion activity through Rab8a. Our results have thus revealed a mechanistic signaling circuit controlling LD fusion and fatty liver formation.

PMID:
25158853
DOI:
10.1016/j.devcel.2014.07.005
[Indexed for MEDLINE]
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