Newly synthesized AIFM1 determines the hypersensitivity of T lymphocytes to STING activation-induced cell apoptosis.

STING is a well-known signaling adaptor essential for sensing cytosolic dsDNA to produce type I interferon. Although the detailed underlying mechanisms remain enigmatic, recent studies show that STING activation can lead to T lymphocyte apoptosis. Here, we report that AIFM1 facilitates STING activation-induced cell apoptosis in T lymphocytes. Mechanistically, AIFM1 is upregulated after STING activation in T cells but not in HEK293T-STING and THP-1 cells, rendering T cells more sensitive to apoptosis. In contrast to the canonical role of AIFM1 in the caspase-independent parthanatos, the function of AIFM1 is operated by the formation of an AIFM1/IRF3/BAX complex and mitochondrial outer membrane permeabilization, which cause cytochrome c release and caspase activation. Furthermore, supplementation with newly synthesized AIFM1 can reconstitute STING activation-induced cell apoptosis in HEK293T-STING and THP-1 cells. Our study identifies AIFM1 as a key regulating factor determining the hypersensitivity of T lymphocytes to STING activation-induced cell apoptosis.