API5 Phosphorylation Promotes Antiviral Immunity by Inhibiting Degradation of Cytosolic RNA Sensor RLRs.

Ubiquitin-mediated selective autophagy is essential for innate immune responses against pathogens. However, the role of apoptosis inhibitor 5 (API5), in governing both ubiquitin-mediated autophagy and antiviral immunity, are poorly defined. Here, it is found that the serine/arginine-rich protein kinase 1 (SRPK1)-dependent phosphorylation of API5 at S464 site is essential for priming antiviral immune responses during diverse RNA virus infection. Mechanistically, phosphorylated API5 forms complexes with autophagic receptor p62 and eliminates itself from ubiquitination at K141, thereby reducing p62 aggregations and inhibiting the autophagic degradation of cytosolic RNA sensors RIG-I and MDA5 to mobilize RLR-mediated antiviral responses. Taken together, it is unveiled that API5 phosphorylation by SRPK1 is required for the inhibition of ubiquitin-mediated autophagic degradation of RNA sensors, revealing a coordinating nature of virus-host interactions that sustains host antiviral defenses.