RAB18 modulates autophagy in human stellate cells.

Affiliation

Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, TX, USA; Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX, USA. Electronic address: [Email]

Abstract

BACKGROUND : Macroautophagy (or autophagy) is a conserved degradative pathway that breaks down sequestered cytoplasmic proteins and organelles in specialized double-membrane compartments called autophagosomes that fuse with lysosomes. Several proteins orchestrate this process, specifically Rab GTPases that are master regulators of molecular trafficking. RAB18 GTPase, a known mediator of stellate cell activation, is known to modulate autophagic flux in fibroblasts. However, its role in autophagy is unexplored in hepatic stellate cells.
OBJECTIVE : The aim of this study was to investigate the role of RAB18 in modulating autophagy in hepatic stellate cells.
METHODS : Role of RAB18 was determined by genetic depletion, pharmacologic inhibition, and overexpression studies to monitor autophagy flux and proteostasis in human LX2 stellate cell line.
RESULTS : RAB18 knockdown increases autophagy flux and regulates proteostasis. LX2 cells stimulated with transforming growth factor-beta robustly increases expression of profibrotic genes such as COL1A1 and ACTA2 along with RAB18 and its guanine nucleotide exchange factor, RAB3GAP1.
CONCLUSIONS : The study elucidates a role for RAB18 in autophagy and regulation of proteostasis in human stellate cells. Molecular insights into this process can provide therapeutic opportunities for intervention in liver fibrosis.

Keywords

Autophagy,Bafilomycin,Canavanine,Fibrosis,Hepatic stellate cells,LC3-II,RAB18,

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