# Dual roles of TRPV2 in the innate immune response to cytosolic DNA: Arresting dormant and boosting activated STING

## TL;DR

TRPV2 controls the STING immune pathway by keeping it inactive when needed and activating it when cytosolic DNA is present.

## Contribution

TRPV2 is identified as a dual regulator of STING dormancy and activation in the innate immune response.

## Key findings

- TRPV2 suppresses spontaneous STING activation in the absence of cytosolic DNA.
- TRPV2 promotes STING activation by releasing Ca2+ from the endoplasmic reticulum upon cytosolic DNA detection.
- TRPV2 regulates type I interferon production and natural killer cell activity via the cGAS/STING pathway.

## Abstract

The cGAS/STING-dependent innate immune pathway is central in the cellular response to cytosolic DNA derived from viral infections, genotoxic stress, or mitochondrial defects. While efficient activation of the pathway is crucial for defending against pathogens and cancer, maintaining its dormancy without stimuli is equally important to avoid autoimmunity. However, the precise control of the cGAS/STING pathway remains poorly understood. Here, we report that the ion channel TRPV2 regulates both the dormancy and activation of STING. TRPV2 associates with STING and suppresses spontaneous STING activation in the absence of cytoDNA but dissociates from STING and promotes its activation by releasing Ca2+ from the endoplasmic reticulum in the presence of cytoDNA, which facilitates STING translocation to Golgi. Consequently, TRPV2 governs type I interferon production and natural killer cell-mediated cytotoxicity through the cGAS/STING pathway. The dual roles of TRPV2 provide an elegant mechanism for a balanced innate immune response.

A tightly controlled innate immune response is vital. Cheng et al. discovered the ion channel TRPV2 as a key regulator of STING-mediated innate immune response. Through their physical interaction, TRPV2 keeps STING dormant; activation by cytosolic DNA triggers their dissociation and ER Ca2+ release, initiating STING signaling.