A RasGAP, DAB2IP, regulates lipid droplet homeostasis by serving as GAP toward RAB40C

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// Xiaomin Luo 1, 2 , Chunman Li 2, * , Ran Tan 3, * , Xiaohui Xu 3 , William K.K. Wu 4 , Ayano Satoh 5 , Tuanlao Wang 3 and Sidney Yu 2, 6 1 Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, P.R. China 2 School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, P.R. China 3 School of Pharmaceutical Sciences, Xiamen University, Fujian, P.R. China 4 Department of Anesthesia, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, P.R. China 5 The Graduate School of Natural Science and Technology, Okayama University, Okayama, Japan 6 Epithelial Cell Biology Research Centre, The Chinese University of Hong Kong, Hong Kong SAR, P.R. China * These authors have contributed equally to this work Correspondence to: Sidney Yu, email: Sidney.yu@cuhk.edu.hk Tuanlao Wang, email: xmuibrwtl@xmu.edu.cn Keywords: lipid droplets, RAB40C, GTPase activating protein, DAB2IP Received: February 08, 2017     Accepted: May 08, 2017     Published: August 03, 2017 ABSTRACT Lipid droplet (LD) homeostasis involves activities of various RAB small GTPases. Recently, we found RAB40C was one of the RAB proteins regulating LD homeostasis. RAB40C contains a unique SOCS domain that is required for clustering of LDs. However, its precise functional role in LD homeostasis and mechanism of regulation remain largely unknown. In this study, we observed over-accumulation of LDs in cells with RAB40C deleted by Crispr-Cas9 editing. RAB40C appeared to reduce LD accumulation after long term incubation of cells with oleic acid (24 hours). Unexpectedly, we found that Ras GTPase activating protein (GAP), DAB2IP, bound to RAB40C mainly via its GAP domain and could serve as RAB40C GAP. Studies involving overexpression of DAB2IP and its GAP defective mutant and siRNA depletion of DAB2IP all confirmed that DAB2IP negatively regulated the effect of RAB40C on LD homeostasis. These results provide a novel perspective on the regulation of RAB40C and implicate various signalling pathways regulated by DAB2IP, which may play a role in LD homeostasis via RAB40C.