Hua Rui, Wei Jinzi, Torres Mauricio, He Yuxin, Li Yanan, Sun Xiaowei, Wang Li, Inoki Ken, Yoshida Sei
State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin, China.
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
J Cell Physiol. 2023 May;238(5):1063-1079. doi: 10.1002/jcp.30996. Epub 2023 Mar 16.
Circular dorsal ruffles (CDRs) are rounded membrane ruffles induced by growth factors to function as precursors of the large-scale endocytosis called macropinocytosis. In addition to their role in cellular uptake, recent research using cell line systems has shown that CDRs/macropinocytosis regulate the canonical AKT-mTORC1 growth factor signaling pathway. However, as CDRs have not been observed in tissues, their physiological relevance has remained unclear. Here, utilizing ultrahigh-resolution scanning electron microscopy, we first report that CDRs are expressed in glomerular podocytes ex vivo and in vivo, and we visually captured the transformation process to macropinocytosis. Moreover, through biochemical and imaging analyses, we show that AKT phosphorylation localized to CDRs upstream of mTORC1 activation in podocyte cell lines and isolated glomeruli. These results demonstrate the physiological role of CDRs as signal platforms for the AKT-mTORC1 pathway in glomerular podocytes at the tissue level. As mTORC1 plays critical roles in podocyte metabolism, and aberrant activation of mTORC1 triggers podocytopathies, our results strongly suggest that targeting CDR formation could represent a potential therapeutic approach for these diseases.
圆形背侧褶皱（CDRs）是由生长因子诱导产生的圆形膜褶皱，作为称为巨胞饮作用的大规模内吞作用的前体发挥作用。除了其在细胞摄取中的作用外，最近使用细胞系系统的研究表明，CDRs/巨胞饮作用调节经典的AKT-mTORC1生长因子信号通路。然而，由于在组织中未观察到CDRs，它们的生理相关性仍不清楚。在这里，利用超高分辨率扫描电子显微镜，我们首次报告CDRs在体外和体内的肾小球足细胞中表达，并且我们直观地捕捉到了向巨胞饮作用的转化过程。此外，通过生化和成像分析，我们表明在足细胞系和分离的肾小球中，AKT磷酸化定位于mTORC1激活上游的CDRs。这些结果证明了CDRs作为组织水平上肾小球足细胞中AKT-mTORC1途径的信号平台所起的生理作用。由于mTORC1在足细胞代谢中起关键作用，并且mTORC1的异常激活会引发足细胞病变，我们的结果强烈表明，靶向CDR形成可能是这些疾病的一种潜在治疗方法。
