The REEP family of proteins: Molecular targets and role in pathophysiology

Receptor expression-enhancing proteins (REEPs) are an evolutionarily conserved protein family that is pivotal to the structure and function of the endoplasmic reticulum (ER). The REEP family can be classified into two major subfamilies in higher species, the REEP1-4 and REEP5-6 subfamilies. Within the REEP1-4 subfamily, REEP1 and REEP2 are closely related, and REEP3 and REEP4 are similarly related. The REEP family is widely distributed in various tissues. Recent studies indicate that the REEP family is involved in many pathological and physiological processes, such as ER morphogenesis and remodeling, microtubule cytoskeleton regulation, and the trafficking and expression of G protein-coupled receptors (GPCRs). Moreover, the REEP family plays crucial roles in the occurrence and development of many diseases, including neurological diseases, diabetes, retinal diseases, cardiac diseases, infertility, obesity, oligoarticular juvenile idiopathic arthritis (OJIA), COVID-19, and cancer. In the present review, we describe the distribution and structure of the REEP family. Furthermore, we summarize the functions and the associated diseases of this family. Based on the pleiotropic actions of the REEP family, the study of its family members is crucial to understanding the relevant pathophysiological processes and developing strategies to modulate and control these related diseases.