CDKL5 regulates p62-mediated selective autophagy and host antiviral defense

Abstract

Virophagy, the selective autophagosomal engulfment and degradation of viral components, is crucial for antiviral immunity. However, the mechanisms leading to viral antigen recognition and autophagy induction remain poorly understood. Here, we identify a novel kinase, Cyclin-dependent kinase-like 5 (CDKL5), as an essential regulator of virophagy. Deletion of CDKL5 or abrogation of its kinase activity reduced virophagy of Sindbis virus (SINV), a neurotropic RNA virus, and increased intracellular accumulation of SINV capsid proteins and cellular cytotoxicity. Mechanistically, through direct phosphorylation of the selective autophagy receptor p62, CDKL5 promoted formation of p62 inclusion bodies that bound capsid. Loss of CDKL5 disrupted the capsid-p62 interaction, and a p62 phosphomimetic mutant rescued the interaction. CDKL5 knockout mice demonstrated increased neuronal cell death after SINV infection and enhanced lethality after infection with several human viruses. Overall, these findings identify a cell-autonomous innate immune mechanism for autophagy activation to clear toxic viral capsid aggregates during infection.