MAVS undergoes aggregation under hypoxia to enhance the hypoxia signaling pathway by promoting the generation of mitochondrial ROS.

The mitochondrial antiviral signaling protein (MAVS) is a key component of the innate immune response against RNA viruses. Its involvement in other cellular stresses is largely unknown. Here, we found that hypoxia induces MAVS aggregation, leading to the stabilization of HIF1/2α proteins and the enhancement of hypoxia signaling. Mechanistic studies revealed that MAVS enhances TRAF6 binding to ECSIT, which catalyzes ECSIT polyubiquitination. This promotes mitochondrial ROS generation and likely inhibits PHD2 enzymatic activity, thereby reducing HIF1/2α proteasomal degradation. Disrupting MAVS in both mice and zebrafish decreased the expression of hypoxia response genes and reduced the tolerance of zebrafish to hypoxia. This study reveals an unexpected role of MAVS in hypoxia signaling.