Rab18: new insights into the function of an essential protein

Abstract

Rab18 is one of the small number of conserved Rab proteins which have been traced to the last eukaryotic common ancestor. It is found in organisms ranging from humans to trypanosomes, and localizes to multiple organelles, including most notably endoplasmic reticulum and lipid droplets. In humans, absence of Rab18 leads to a severe illness known as Warburg-Micro syndrome. Despite this evidence that Rab18 is essential, its role in cells remains mysterious. However, recent studies identifying effectors and interactors of Rab18, are now shedding light on its mechanism of action, suggesting functions related to organelle tethering and to autophagy. In this review, we examine the variety of roles proposed for Rab18 with a focus on new evidence giving insights into the molecular mechanisms it utilizes. Based on this summary of our current understanding, we identify priority areas for further research.

Keywords: Lipid droplets; Lipid metabolism; Rab18; Secretion; Small GTPases; Tethering; Warburg-Micro syndrome.

Fig. 1

Some reported functions of Rab18. Each of these functions is described at greater length in the main text

Fig. 2

Schematic showing the major known players in the Rab18 GTP cycle

Fig. 3

Current model for Rab18/NRZ-mediated tethering of lipid droplets to endoplasmic reticulum. In this model, Rab18 on the LD membrane recruits the NRZ complex consisting of NAG, ZW10 and RINT. Elements of the NRZ complex in turn bind to SNARE proteins (Use1 and BN1 P1) found in ER membranes. Also shown is Rab18 on ER membranes recruiting fatty acid synthase, which could favor enlargement of lipid droplets. Whether Rab18 on ER membranes could also recruit NRZ complex, and whether this complex could participate in tethering interactions, has not been addressed