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CDKL5 regulates p62-mediated selective autophagy and confers protection against neurotropic viruses
Josephine W. Thinwa, … , Tiffany A. Reese, Michael U. Shiloh
Josephine W. Thinwa, … , Tiffany A. Reese, Michael U. Shiloh
Published November 2, 2023
Citation Information: J Clin Invest. 2024;134(1):e168544. https://doi.org/10.1172/JCI168544.
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Research Article Infectious disease Virology Article has an altmetric score of 14

CDKL5 regulates p62-mediated selective autophagy and confers protection against neurotropic viruses

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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.

Authors

Josephine W. Thinwa, Zhongju Zou, Emily Parks, Salwa Sebti, Kelvin Hui, Yongjie Wei, Mohammad Goodarzi, Vibha Singh, Greg Urquhart, Jenna L. Jewell, Julie K. Pfeiffer, Beth Levine, Tiffany A. Reese, Michael U. Shiloh

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Figure 8

CDKL5 is required for SINV virophagy in vivo.

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CDKL5 is required for SINV virophagy in vivo.
Seven-day-old CDKL5-WT and...
Seven-day-old CDKL5-WT and CDKL5-KO mice were infected intracerebrally with SINV strain dsTE12Q (1 × 103 PFU). (A–E) Brains were harvested on the indicated days after infection. (A) The presence of SINV capsid–positive cells was determined by immunohistochemistry. Representative light micrographs of capsid by immunohistochemistry. Scale bar: 100 μm. (B) Quantification of capsid+ (Ag+) cells per section of brain. Bars represent mean ± SEM of 7–8 mice per group. (C) Identification of apoptotic cells in brains sections using TUNEL assay. Representative light micrographs. Scale bar: 200 μm. (D) Quantification of TUNEL-positive cells per area of brain. Bars represent mean ± SEM of 7–8 mice per group. (E) Viral titers from brain homogenates processed on the indicated days after infection. Bars represent mean ± SEM of 7–8 mice per group. (F) Brains from mice either mock inoculated (HBSS) or inoculated with SINV were harvested 7 days after infection. Brain homogenates were subjected to immunoblotting using the indicated antibodies. (G) Densitometry analysis of individual mice of p-T269/S272 normalized to total p62 and LC3-II normalized to actin. Dots represent individual mice. Bars on graph represent mean ± SEM of 3 or 5 mice per genotype for control and infected mice, respectively. All P values were determined by Mann-Whitney U test. *P < 0.05, **P < 0.01, ***P < 0.001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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