Article ; Online: CDKL5 regulates p62-mediated selective autophagy and confers protection against neurotropic viruses.
The Journal of clinical investigation
2024 Volume 134, Issue 1
Abstract: Virophagy, the selective autophagosomal engulfment and lysosomal degradation of viral components, is crucial for neuronal cell survival and antiviral immunity. However, the mechanisms leading to viral antigen recognition and capture by autophagic ... ...
| Abstract | Virophagy, the selective autophagosomal engulfment and lysosomal degradation of viral components, is crucial for neuronal cell survival and antiviral immunity. However, the mechanisms leading to viral antigen recognition and capture by autophagic machinery remain poorly understood. Here, we identified cyclin-dependent kinase-like 5 (CDKL5), known to function in neurodevelopment, as an essential regulator of virophagy. Loss-of-function mutations in CDKL5 are associated with a severe neurodevelopmental encephalopathy. We found that deletion of CDKL5 or expression of a clinically relevant pathogenic mutant of CDKL5 reduced virophagy of Sindbis virus (SINV), a neurotropic RNA virus, and increased intracellular accumulation of SINV capsid protein aggregates and cellular cytotoxicity. Cdkl5-knockout mice displayed increased viral antigen accumulation and neuronal cell death after SINV infection and enhanced lethality after infection with several neurotropic viruses. Mechanistic studies demonstrated that CDKL5 directly binds the canonical selective autophagy receptor p62 and phosphorylates p62 at T269/S272 to promote its interaction with viral capsid aggregates. We found that CDKL5-mediated phosphorylation of p62 facilitated the formation of large p62 inclusion bodies that captured viral capsids to initiate capsid targeting to autophagic machinery. Overall, these findings identify a cell-autonomous innate immune mechanism for autophagy activation to clear intracellular toxic viral protein aggregates during infection. |
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| MeSH term(s) | Mice ; Animals ; Protein Aggregates ; Viruses ; Autophagy/genetics ; Phosphorylation ; Mice, Knockout ; Capsid Proteins ; Antigens, Viral ; Protein Serine-Threonine Kinases/genetics |
| Chemical Substances | Protein Aggregates ; Capsid Proteins ; Antigens, Viral ; CDKL5 protein, mouse (EC 2.7.11.22) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) |
| Language | English |
| Publishing date | 2024-01-02 |
| Publishing country | United States |
| Document type | Journal Article |
| ZDB-ID | 3067-3 |
| ISSN | 1558-8238 ; 0021-9738 |
| ISSN (online) | 1558-8238 |
| ISSN | 0021-9738 |
| DOI | 10.1172/JCI168544 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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