Biochemistry and Molecular Biology Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA.
Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA.
J Cell Sci. 2020 Jun 11;133(11):jcs236661. doi: 10.1242/jcs.236661.
Epithelial cells, such as liver-resident hepatocytes, rely heavily on the Rab family of small GTPases to perform membrane trafficking events that dictate cell physiology and metabolism. Not surprisingly, disruption of several Rab proteins can manifest in metabolic diseases or cancer. Rab32 is expressed in many secretory epithelial cells but its role in cellular metabolism is virtually unknown. In this study, we find that Rab32 associates with lysosomes and regulates proliferation and cell size of Hep3B hepatoma and HeLa cells. Specifically, we identify that Rab32 supports the mechanistic target of rapamycin complex 1 (mTORC1) signaling under basal and amino acid-stimulated conditions. Consistent with inhibited mTORC1, an increase in nuclear TFEB localization and lysosome biogenesis is also observed in Rab32-depleted cells. Finally, we find that Rab32 interacts with mTOR kinase, and that loss of Rab32 reduces the association of mTOR and mTORC1 pathway proteins with lysosomes, suggesting that Rab32 regulates lysosomal mTOR trafficking. In summary, these findings suggest that Rab32 functions as a novel regulator of cellular metabolism through supporting mTORC1 signaling.This article has an associated First Person interview with the first author of the paper.
上皮细胞，如肝脏驻留的肝细胞，严重依赖 Rab 家族的小分子 GTPases 来执行决定细胞生理和代谢的膜运输事件。毫不奇怪，几种 Rab 蛋白的破坏可能表现为代谢疾病或癌症。Rab32 在许多分泌上皮细胞中表达，但它在细胞代谢中的作用几乎未知。在这项研究中，我们发现 Rab32 与溶酶体相关，并调节 Hep3B 肝癌细胞和 HeLa 细胞的增殖和细胞大小。具体来说，我们确定 Rab32 在基础和氨基酸刺激条件下支持雷帕霉素靶蛋白复合物 1（mTORC1）信号。与抑制的 mTORC1 一致，在 Rab32 耗尽的细胞中还观察到核 TFEB 定位和溶酶体生物发生的增加。最后，我们发现 Rab32 与 mTOR 激酶相互作用，并且 Rab32 的缺失减少了 mTOR 和 mTORC1 途径蛋白与溶酶体的关联，表明 Rab32 调节溶酶体 mTOR 运输。总之，这些发现表明 Rab32 通过支持 mTORC1 信号作为细胞代谢的新型调节剂发挥作用。本文有一篇与该论文第一作者的相关第一人称采访。
