The RAB GTPase RAB18 modulates macroautophagy and proteostasis

Biochem Biophys Res Commun. 2017 May 6;486(3):738-743. doi: 10.1016/j.bbrc.2017.03.112. Epub 2017 Mar 22.

Abstract

Macroautophagy is a conserved degradative pathway and its deterioration is linked to disturbances in cellular proteostasis and multiple diseases. Here, we show that the RAB GTPase RAB18 modulates autophagy in primary human fibroblasts. The knockdown of RAB18 results in a decreased autophagic activity, while its overexpression enhances the degradative pathway. Importantly, this function of RAB18 is dependent on RAB3GAP1 and RAB3GAP2, which might act as RAB GEFs and stimulate the activity of the RAB GTPase. Moreover, the knockdown of RAB18 deteriorates proteostasis and results in the intracellular accumulation of ubiquitinated degradation-prone proteins. Thus, the RAB GTPase RAB18 is a positive modulator of autophagy and is relevant for the maintenance of cellular proteostasis.

Keywords: Autophagy; Proteostasis; RAB18; RAB3GAP1; RAB3GAP2; Warburg Micro syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy / genetics*
  • Fibroblasts / cytology
  • Fibroblasts / metabolism*
  • Gene Expression Regulation
  • Genes, Reporter
  • Humans
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Primary Cell Culture
  • Protein Stability
  • Proteolysis
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Red Fluorescent Protein
  • Signal Transduction
  • rab GTP-Binding Proteins / antagonists & inhibitors
  • rab GTP-Binding Proteins / genetics*
  • rab GTP-Binding Proteins / metabolism
  • rab3 GTP-Binding Proteins / genetics*
  • rab3 GTP-Binding Proteins / metabolism

Substances

  • Luminescent Proteins
  • RAB18 protein, human
  • RAB3GAP2 protein, human
  • RNA, Small Interfering
  • Recombinant Fusion Proteins
  • RAB3GAP1 protein, human
  • rab GTP-Binding Proteins
  • rab3 GTP-Binding Proteins