The Xkr protein family—From apoptosis executors to diverse physiological functions regulators

The asymmetry of the phospholipids in the cell membrane is fundamental to maintaining normal cellular physiological functions. Phosphatidylserine (PS), a key phospholipid, is typically restricted to the inner side of the plasma membrane. However, during specific physiological or pathological processes such as apoptosis, PS rapidly flips to the cell surface, serving as an 'eat me' signal that mediates apoptotic cells' recognition. This process is catalyzed by a class of membrane proteins known as 'scramblases'. The Xk-related (Xkr) protein family, particularly Xkr8, has been identified as the main scramblase during apoptosis. As research has progressed in recent years, the functions of other Xkr family members (such as Xkr4 and Xkr9) have gradually come to light. They not only participate in apoptosis, but also play vital roles in various life processes, including nervous system development, auditory formation and tumor immunity. This article systematically reviews the discovery, molecular structure, activation mechanisms, and current research on the Xkr protein family. We also discuss future research directions, aiming to provide a comprehensive understanding of the functional diversity and regulatory networks of this emerging protein family.