The recently identified
anion channel LRRC8 volume-regulated
anion channels (VRACs) are heteromeric hexamers constituted with the obligate LRRC8A subunit paired with at least one of the accessory LRRC8B to LRRC8E subunits. In addition to transport
chloride,
taurine, and
glutamate, LRRC8 VRACs also transport the
anticancer agent cisplatin and
STING agonists 2'3'-cyclic GMP-
AMP (
cGAMP) and cyclic dinucleotides; hence, they are implicated in a variety of physiological and
pathological processes, such as cell swelling,
stroke,
cancer, and
viral infection. Although the subunit composition largely determines VRAC substrate specificity, the opening of various VRAC pores under physiological and pathological settings remains enigmatic. In this study, we demonstrated that VRACs comprising LRRC8A and LRRC8E (LRRC8A/E-containing VRACs), specialized in
cGAMP transport, can be opened by a
protein component present in serum under resting condition. Serum depletion ablated the tonic activity of LRRC8A/E-containing VRACs, decreasing
cGAMP transport in various human and murine cells. Also, heating or
proteinase K treatment abolished the ability of serum to activate VRAC. Genetic analyses revealed a crucial role for
cGAMP synthase (cGAS) in serum/TNF-promoted VRAC activation. Notably, the presence of cGAS on the plasma membrane, rather than its
DNA-binding or enzymatic activity, enabled VRAC activation. Moreover,
phospholipid PIP2 seemed to be instrumental in the membrane localization of cGAS and its association with VRACs. Corroborating a role for LRRC8A/D-containing VRACs in
cisplatin transport, serum and TNF markedly potentiated
cisplatin uptake and killing of
cancer cells derived from human or mouse. Together, these observations provide new insights into the complex regulation of VRAC activation and suggest a novel approach to enhance the efficacy of
cGAMP and
cisplatin in treating
infection and
cancer.