Ca2+ is an intracellular danger signal promoting STING activation
Nov. 04, 2026
Prof. Zhengfan Jiang published a paper in Molecular Cell.
Calcium release in host cells is essential for viral infection and survival, and mutations disrupting calcium homeostasis are associated with chronic viral infections or autoimmune diseases in patients, yet the biological significance of calcium (Ca2+) signaling on stimulator of interferon genes (STING) activation remains unclear. Here, we show that cytosolic Ca2+ is sensed by host cells as an immediate-early danger signal. Viral infection-activated Rho GTPases and phospholipase C-β (PLCβ) induce ITPR-mediated endoplasmic reticulum (ER) Ca2+ release, while STING translocation induces TRPV2-mediated ER Ca2+ release, both leading to store-operated Ca2+ entry (SOCE) through ORAI channels. Ca2+ influx activates calmodulin (CaM)-dependent protein kinases CaMKK and CaMK1D. Activated CaMK1D phosphorylates STING, allowing for TBK1 trans-autophosphorylation. Inhibiting Ca2+ signaling or mutating CaMK1D-phosphorylating STING sites impairs STING activation. Consistently, Ca2+ signaling is important for the host defense against DNA viruses in mice. These results support a two-signal mode for STING activation in which the Ca2+-CaM-CaMKK-Ca2+/calmodulin-dependent protein kinase (CaMK) cascade is indispensable.
Original Link: https://www.cell.com/molecular-cell/abstract/S1097-2765(26)00713-6