CORO1C (coronin 1C) promotes autophagosome formation by coordinating branched actin network dynamics

Macroautophagy/autophagy is a critical cellular process that maintains the cellular homeostasis by degrading and recycling cytotoxic material. Despite its importance, the intricate mechanisms governing this process remain partially elusive. Here, we designed and performed a genome-wide loss-of-function screen on a mouse haploid ESC mutant library and identified the actin-binding protein CORO1C (coronin 1C) as a previously unrecognized regulator of mammalian autophagy. Interactions between CORO1C and the ACTR2/ARP2 (actin related protein 2)-ACTR3/ARP3 complex are essential for branched actin network assembly, SQSTM1/p62 body formation, and maintaining autophagosome structural integrity. Unlike CORO1A and CORO1B, CORO1C possesses a unique second actin-binding site involved in regulating the branched actin network and autophagic process. Notably, coro1c-/- newborn mice died earlier in starvation than wild-type littermates and multiple tissues showed autophagy-deficient phenotypes. Moreover, the adult coro1c-deficient mice exhibit severe spatial learning memory impairment. Collectively, our research uncovered the surprising role of CORO1C in promoting the formation of branched actin network and its central role in the assembly of structures vital to autophagy.