Invisible leashes: the tethering VAP proteins from infectious diseases to neurodegeneration

Abstract Intracellular organelles do not, as thought for a long time, act in isolation but are dynamically tethered together by entire machines responsible for inter-organelle trafficking and positioning. Among the proteins responsible for tethering is the family of vesicle-associated proteins (VAPs) that appear in all eukaryotes and are localized primarily in the endoplasmic reticulum. The major functional role of VAP proteins is to tether the endoplasmic reticulum with different organelles, and regulate lipid metabolism and transport. VAP proteins have gained increasing attention because of their role in human pathology where they contribute to infections by viruses and bacteria, and participate in neurodegeneration. In this review, we discuss the structure, evolution and functions of VAP proteins, focusing more specifically on VAP-B for its relationship with amyotrophic lateral sclerosis and other neurodegenerative diseases.