HTATSF1 regulates innate antiviral immune response by orchestrating TRAF3-IRF3 and TRAF6-NF-κB pathways.

Upon infection, viral DNA/RNA is detected by cGAS/RIG-I-like receptors, triggering the adaptor MITA/STING- or VISA/MAVS-dependent innate antiviral immune response respectively. Both adaptors recruit the conserved TRAF3 and TRAF6 to activate TBK1-IRF3 and TAK1-NF-κB pathways respectively, leading to collaborative induction of antiviral effector genes. How the functions of TRAF3 and TRAF6 bifurcate in innate antiviral signaling remains enigmatic. We identified HTATSF1 as a positive regulator of virus-triggered innate antiviral response. Upon viral infection, HTATSF1 promotes HECTD3-catalyzed K63-linked polyubiquitination of TRAF3, leading to its recruitment of TBK1 and activation of IRF3. In contrast, HTATSF1 promotes recruitment of TAK1 to TRAF6 and activation of the TAK1-IKK-NF-κB axis independently of HECTD3. HTATSF1-deficiency impairs induction of downstream antiviral genes, and HTATSF1-deficient mice exhibit decreased cytokine production and increased mortality upon viral infection. Our findings demonstrate that HTATSF1 is an essential regulator of innate antiviral immune response by orchestrating the TRAF3-IRF3 and TRAF6-NF-κB pathways.