Mitochondrial Fis1 tunes Rab7A activity via TBC1D15 modulating STING degradation

Abstract

SUMMARY The mechanisms governing the final trafficking steps of the cyclic dinucleotide innate immune receptor stimulator of interferon genes (STING) are not fully understood. Here, we identify the mitochondrial protein Fis1 as a regulator of STING endolysosomal degradation. The absence of Fis1 in HeLa cells stabilizes STING, boosting downstream signaling without affecting its initial endoplasmic reticulum (ER)-to-Golgi traffic. Instead, Fis1 loss impairs STING delivery to endolysosomes. Fis1 recruits the Rab7A-GAP TBC1D15 to mitochondria and upon STING activation, TBC1D15 localization shifts to the Golgi. In the absence of Fis1, the interaction between TBC1D15 and Rab7A is disrupted, leading to decreased Rab7A GTPase activity and impaired STING degradation. Our findings reveal a mitochondria-controlled axis where Fis1 tunes Rab7A activity via TBC1D15, which is required to ensure proper STING degradation, directly linking mitochondria to lysosomal trafficking and the termination of innate immune signaling.