Unconventional protein secretion: Exploring membrane proteins and beyond

Protein secretion is essential for cellular communication and function, enabling the delivery of both soluble and integral membrane proteins to the extracellular space and the cell surface. While the classical endoplasmic reticulum (ER)–Golgi pathway has been extensively studied, emerging evidence highlights the existence of unconventional protein secretion (UcPS) pathways. Among these, the mechanisms that enable membrane proteins to bypass the Golgi apparatus remain poorly understood. In this review, I discuss recent advances that shed light on the processes governing Golgi-bypassing membrane secretion. These findings reveal that UcPS of membrane proteins is evolutionarily conserved, operates under both physiological and stress conditions, and involves diverse intermediate carriers and molecular players. Looking ahead, advances in technology and the development of more sophisticated functional assays, along with in vivo models, are expected to further unravel the molecular mechanisms and biological roles of these unconventional pathways.