Recent advances in the structure, function and regulation of the volume-regulated anion channels and their role in immunity

Volume-regulated anion channels (VRACs) are heteromeric complexes formed by proteins of the leucine-rich repeat-containing 8 (LRRC8) family. LRRC8A (also known as SWELL1) is the core subunit required for VRAC function, and it must combine with one or more of the other paralogues (i.e. LRRC8B-E) to form functional heteromeric channels. VRACs were discovered in T lymphocytes over 35 years ago and are found in virtually all vertebrate cells. Initially, these anion channels were characterized for their role in Cl^- efflux during the regulatory volume decrease process triggered when cells are subjected to hypotonic challenges. However, substantial evidence suggests that VRACs also transport small molecules under isotonic conditions. These findings have expanded the research on VRACs to explore their functions beyond volume regulation. In innate immune cells, VRACs promote inflammation by modulating the transport of immunomodulatory cyclic dinucleotides, itaconate and ATP. In adaptive immune cells, VRACs suppress their function by taking up cyclic dinucleotides to activate the STING signalling pathway. In this review, we summarize the current understanding of LRRC8 proteins in immunity and discuss recent progress in their structure, function, regulation and mechanisms for channel activation and gating. Finally, we also examine potential immunotherapeutic applications of VRAC modulation.