The role of ARF1 in unconventional secretion of transmembrane protein

Abstract

The majority of transmembrane proteins are conventionally transported through the endoplasmic reticulum (ER) to the Golgi apparatus and then to the plasma membrane. However, studies have shown that some proteins can reach the plasma membrane via an alternative route known as the unconventional protein secretion (UPS) pathway. Despite ongoing research, the underlying molecular mechanism of UPS has yet to be elucidated. This study reveals that the UPS of transmembrane protein requires ARF1 activation. An ARF1-GTP-restricted mutant powerfully rescues cystic fibrosis transmembrane conductance regulator (CFTR) and full-length Spike (S) protein on the plasma membrane. Conversely, gene silencing of ARF1 blocks unconventional trafficking of CFTR and S protein. Activated ARF1 interacts with OSBPL1 and VAPA, forming an ARF1-OSBPL1-VAPA complex that induces autophagosome formation near CFTR trapped in the ER. These results suggest that ARF1 plays a key role in Golgi-bypassing trafficking of transmembrane proteins.