Abstract

Genotoxic stress caused by DNA damage or replication obstruction triggers a multitude of cellular pathways to maintain chromosomal stability or drive cell death. The release of DNA fragments into cytosol during such stress also activates the cGAS/STING-dependent innate immune response, which in turn regulates various cellular processes such as immune activation, senescence and autophagy. However, despite its importance, how these pathways and processes are controlled and properly coordinated remains poorly understood. We have recently identified a novel genome protection pathway in the replication stress response, which intersects with both the cGAS/STING axis and the Ca2+/CaMKK2/AMPK cascade. Disruption of this pathway causes excessive replication fork processing, chromosomal instability, and cell death. Central to this signaling pathway is the interplay between STING and the TRPV2 ion channel on the ER. Under normal conditions, STING associates with TRPV2 and represses its channel activity to prevent spurious Ca2+ release in the absence of cytosolic DNA. When cytosolic DNA is present, the binding of the cGAS-produced cGAMP to STING causes its dissociation from TRPV2, leading to TRPV2 derepression, Ca2+ release and downstream pathway activation. Intriguingly, we have found that TRPV2 also reciprocally regulates STING activation. This mechanistic coupling between STING activation and TRPV2-mediated Ca2+ release allows for precise coordination between the innate immune response and Ca2+-regulated cellular processes. In this talk, I will discuss the role of TRPV2 and intracellular Ca2+ in controlling STING activation and the implications of these regulatory mechanisms for cancer treatment.