Feldmann Anne, Bekbulat Fazilet, Huesmann Heike, Ulbrich Sarah, Tatzelt Jörg, Behl Christian, Kern Andreas
Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, 55099 Mainz, Germany.
Department of Biochemistry of Neurodegenerative Diseases, Institute of Biochemistry und Pathobiochemistry, Ruhr University Bochum, 44801 Bochum, Germany.
Biochem Biophys Res Commun. 2017 May 6;486(3):738-743. doi: 10.1016/j.bbrc.2017.03.112. Epub 2017 Mar 22.
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.
巨自噬是一种保守的降解途径，其功能衰退与细胞蛋白质稳态紊乱及多种疾病相关。在此，我们表明RAB GTP酶RAB18可调节原代人成纤维细胞中的自噬。敲低RAB18会导致自噬活性降低，而其过表达则增强降解途径。重要的是，RAB18的这一功能依赖于RAB3GAP1和RAB3GAP2，它们可能作为RAB鸟嘌呤核苷酸交换因子（GEF）并刺激RAB GTP酶的活性。此外，敲低RAB18会破坏蛋白质稳态并导致泛素化的易降解蛋白在细胞内积累。因此，RAB GTP酶RAB18是自噬的正向调节因子，与维持细胞蛋白质稳态相关。
