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.

Conclusion

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.

中文翻译：

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RAB18调节人星状细胞中的自噬。

背景

巨自噬（或称自噬）是一种保守的降解途径，可分解被称为自噬小体并与溶酶体融合的特化双膜区室中的隔离的胞质蛋白和细胞器。几种蛋白质协调了这一过程，特别是Rab GTPases，它们是分子运输的主要调节剂。RAB18 GTPase是星状细胞激活的已知介体，可调节成纤维细胞中的自噬通量。但是，它在自噬中的作用尚未在肝星状细胞中探索。

客观的

这项研究的目的是调查RAB18在调节肝星状细胞自噬中的作用。

方法

RAB18的作用是通过遗传耗竭，药理学抑制和过度表达研究来监测人LX2星状细胞系中自噬通量和蛋白稳态的结果。

结果

RAB18敲低可增加自噬通量并调节蛋白稳定。转化生长因子-β刺激的LX2细胞与RAB18及其鸟嘌呤核苷酸交换因子RAB3GAP1一起强烈增强了原纤维化基因（如COL1A1和ACTAACT2）的表达。

结论

这项研究阐明了RAB18在人类星状细胞中自噬和蛋白稳态调节中的作用。对该过程的分子见解可以为肝纤维化的介入提供治疗机会。