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

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.

Regulation of lipid homeostasis by the TBC protein dTBC1D22 via modulation of the small GTPase Rab40 to facilitate lipophagy

“…Rab40B has been recently reported to regulate EPLIN and actin cytoskeleton dynamics (Linklater et al, 2021). Rab40C interacts with LDs and modulates LD biogenesis and mobilization (Luo et al, 2017;Tan et al, 2013). We demonstrated that the Drosophila Rab40 promote lipophagy process by regulating Golgi organization and the distribution of lysosomal protein Lamp1.…”

Interactions of Lipid Droplets with the Intracellular Transport Machinery

“…There is no evidence to date for a role of Rab40a and Rab40b on LDs. However, Rab40c has been reported on LDs, and deletion of Rab40c or overexpression of its GTPase activating protein (GAP) disabled homologue 2 interacting protein (DAB2IP) caused accumulation of LDs [58,59]. While the role of Rab40c in LDs is unknown, there are reports linking it to degradation of other proteins.…”

Regulation of GTPase function by autophosphorylation

“…3 (Gasper et al, 2010;Kontani et al, 2002;Ogita et al, 2015). 4 (Luo et al, 2017). 5 (Nobes et al, 1998).…”

“…13 (Jacob et al, 2016;Li et al, 2015). 14 (Lee et al, 2007;Luo et al, 2017;Rodriguez-Gabin et al, 2004). 15 (Mouly et al, 2019;Okada et al, 2015;Riou et al, 2010).…”