NRF1 ‐mediated mitochondrial biogenesis antagonizes innate antiviral immunity

Abstract

Mitochondrial biogenesis is the process of generating new mitochondria to maintain cellular homeostasis. Here, we report that viruses exploit mitochondrial biogenesis to antagonize innate antiviral immunity. We found that nuclear respiratory factor‐1 (NRF1), a vital transcriptional factor involved in nuclear‐mitochondrial interactions, is essential for RNA (VSV) or DNA (HSV‐1) virus‐induced mitochondrial biogenesis. NRF1 deficiency resulted in enhanced innate immunity, a diminished viral load, and morbidity in mice. Mechanistically, the inhibition of NRF1‐mediated mitochondrial biogenesis aggravated virus‐induced mitochondrial damage, promoted the release of mitochondrial DNA (mtDNA), increased the production of mitochondrial reactive oxygen species (mtROS), and activated the innate immune response. Notably, virus‐activated kinase TBK1 phosphorylated NRF1 at Ser318 and thereby triggered the inactivation of the NRF1‐TFAM axis during HSV‐1 infection. A knock‐in (KI) strategy that mimicked TBK1‐NRF1 signaling revealed that interrupting the TBK1‐NRF1 connection ablated mtDNA release and thereby attenuated the HSV‐1‐induced innate antiviral response. Our study reveals a previously unidentified antiviral mechanism that utilizes a NRF1‐mediated negative feedback loop to modulate mitochondrial biogenesis and antagonize innate immune response. image Mitochondrial damage, which can occur during viral infection, results in the release of damage‐associated molecular patterns (DAMPs) and can drive innate antiviral immunity via multiple pathways. Here, inhibition of NRF1‐mediated mitochondrial biogenesis was found to aggravate virus‐induced mitochondrial damage and promote innate antiviral immunity by enhancing mitochondrial DAMPs release. RNA and DNA viral infection activates NRF1‐mediated mitochondrial biogenesis in mouse and human immune cells. Deficiency of NRF1‐mediated mitochondrial biogenesis enhanced innate antiviral response in mice. Mitochondrial DAMPs, promoted by NRF1 deficiency, contribute to innate antiviral immunity. TBK1‐induced NRF1 phosphorylation is physiologically important to host antiviral response.