Ca(2+) is an intracellular danger signal promoting STING activation.

Cytosolic Ca2+ acts as an immediate-early danger signal that promotes STING activation via a CaM–CaMKK–CaMK1D pathway, enabling STING phosphorylation and TBK1 activation.

• Why it matters: Although Ca2+ homeostasis is linked to chronic viral infections and autoimmune disease, how Ca2+ signaling regulates STING activation was unclear.
• What they did: The study mapped a two-signal mechanism: viral Rho GTPases/PLCβ and STING translocation trigger ITPR- and TRPV2-mediated ER Ca2+ release, driving SOCE through ORAI channels and CaMKK/CaMK1D-dependent STING phosphorylation.
• The result: Blocking Ca2+ signaling or mutating CaMK1D-phosphorylating STING sites impaired STING activation, and Ca2+ signaling was important for host defense against DNA viruses in mice.

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