Orofiamma Laura A, Delos Santos Ralph Christian, Mehrabi Ayshin, Leshchyshyn Nikol, Hesketh Geoffrey G, Rahmani Sadia, Patel Aesha, Fekri Farnaz, Ata Rehman, Ratcliffe Colin D H, Crupi Mathieu J F, Mulligan Lois, Park Morag, Gingras Anne-Claude, Antonescu Costin N
Department of Chemistry and Biology, Toronto Metropolitan University, Toronto, ON, Canada.
Graduate Program in Molecular Science, Toronto Metropolitan University, Toronto, ON, Canada.
iScience. 2025 Jul 17;28(8):113131. doi: 10.1016/j.isci.2025.113131. eCollection 2025 Aug 15.
The cell surface abundance of many proteins is controlled by clathrin-mediated endocytosis (CME). CME is driven by the assembly of clathrin and other proteins on the inner leaflet of the plasma membrane into clathrin-coated pits (CCPs). Regulation of CCP dynamics allows for control of the function of specific cell surface proteins, impacting a range of cellular outcomes. AMP-activated protein kinase (AMPK) becomes activated upon metabolic insufficiency and facilitates cellular adaptation to nutrient stress. Here, we examined how AMPK regulates CME and the cell surface membrane traffic of β1-integrin. We find that AMPK controls CCP dynamics and regulates the abundance of the endocytic adaptor protein Dab2 within CCPs in a manner that requires the GTPase Arf6, thus selectively promoting the CCP recruitment and internalization of β1-integrin. This study reveals a signaling pathway for cargo-selective metabolic regulation of CME by AMPK that impacts the function of cell surface proteins such as integrins.
许多蛋白质的细胞表面丰度受网格蛋白介导的内吞作用（CME）调控。CME由网格蛋白和其他蛋白质在质膜内小叶上组装成网格蛋白包被小窝（CCP）所驱动。CCP动态变化的调控有助于控制特定细胞表面蛋白的功能，影响一系列细胞结果。AMP激活的蛋白激酶（AMPK）在代谢不足时被激活，并促进细胞对营养应激的适应。在此，我们研究了AMPK如何调节CME以及β1整合素的细胞表面膜运输。我们发现，AMPK通过一种需要GTP酶Arf6的方式来控制CCP动态变化，并调节CCP内吞作用衔接蛋白Dab2的丰度，从而选择性地促进β1整合素的CCP募集和内化。这项研究揭示了一条由AMPK对CME进行货物选择性代谢调控的信号通路，该通路影响诸如整合素等细胞表面蛋白的功能。
