Misri Gunjan, Murakonda Ajay B, Naslavsky Naava, Caplan Steve
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Traffic. 2025 Jul-Sep;26(7-9):e70015. doi: 10.1111/tra.70015.
Recycling endosomes are essential for membrane trafficking, retrieving internalized cell surface receptors and lipids to the plasma membrane. In this study, we investigate the dynamics of tubular recycling endosomes (TREs) and their regulation. We demonstrate that TREs are highly dynamic structures that first undergo biogenesis and later fission upon internalization of CD98, a known clathrin-independent cargo. Our findings identify two new constituents and novel regulators of TRE function, CD2AP and CIN85, which are recruited to TRE through interactions with MICAL-L1 via their SH3 domains. Depletion of either CD2AP or CIN85 impairs recycling, demonstrating that these proteins play important roles in TRE function. Our study highlights the importance of coordinated protein interactions in maintaining endosomal function and identifies CD2AP and CIN85 as key regulators of the recycling pathway, potentially through their impact on the actin cytoskeleton. Understanding these mechanisms provides new insights into membrane trafficking and may have implications for diseases where endosomal recycling is disrupted.
再循环内体对于膜运输、将内化的细胞表面受体和脂质回收至质膜至关重要。在本研究中，我们研究了管状再循环内体（TREs）的动态变化及其调控机制。我们证明，TREs是高度动态的结构，首先经历生物发生，随后在已知的不依赖网格蛋白的货物CD98内化时发生裂变。我们的研究结果确定了TRE功能的两个新成分和新型调节因子CD2AP和CIN85，它们通过其SH3结构域与MICAL-L1相互作用而被招募到TREs。CD2AP或CIN85的缺失会损害再循环，表明这些蛋白质在TRE功能中发挥重要作用。我们的研究强调了协调的蛋白质相互作用在维持内体功能中的重要性，并确定CD2AP和CIN85是再循环途径的关键调节因子，可能是通过它们对肌动蛋白细胞骨架的影响。了解这些机制为膜运输提供了新的见解，可能对那些内体再循环被破坏的疾病具有启示意义。
