Cholesterol-rich lysosomes induced by respiratory syncytial virus promote viral replication by blocking autophagy flux.

Autor: Chen L; State Key Laboratory of Bioactive Molecules and Druggability Assessment & College of Pharmacy, Jinan University, Guangzhou, China.; Department of Dermatology, The First Affiliated Hospital, Jinan University, Guangzhou, China., Zhang J; State Key Laboratory of Bioactive Molecules and Druggability Assessment & College of Pharmacy, Jinan University, Guangzhou, China., Xu W; State Key Laboratory of Bioactive Molecules and Druggability Assessment & College of Pharmacy, Jinan University, Guangzhou, China., Chen J; State Key Laboratory of Bioactive Molecules and Druggability Assessment & College of Pharmacy, Jinan University, Guangzhou, China., Tang Y; State Key Laboratory of Bioactive Molecules and Druggability Assessment & College of Pharmacy, Jinan University, Guangzhou, China., Xiong S; State Key Laboratory of Bioactive Molecules and Druggability Assessment & College of Pharmacy, Jinan University, Guangzhou, China., Li Y; State Key Laboratory of Bioactive Molecules and Druggability Assessment & College of Pharmacy, Jinan University, Guangzhou, China., Zhang H; Department of Dermatology, The First Affiliated Hospital, Jinan University, Guangzhou, China. tzhangh@jnu.edu.cn., Li M; State Key Laboratory of Bioactive Molecules and Druggability Assessment & College of Pharmacy, Jinan University, Guangzhou, China. jnulimanmei1209@126.com., Liu Z; State Key Laboratory of Bioactive Molecules and Druggability Assessment & College of Pharmacy, Jinan University, Guangzhou, China. tliuzh@jnu.edu.cn.; Guangdong Provincial Key Laboratory of Bioengineering Medicine & College of Life Science and Technology, Jinan University, Guangzhou, China. tliuzh@jnu.edu.cn.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Jul 26; Vol. 15 (1), pp. 6311. Date of Electronic Publication: 2024 Jul 26.
DOI: 10.1038/s41467-024-50711-4
Abstrakt: Respiratory syncytial virus (RSV) hijacks cholesterol or autophagy pathways to facilitate optimal replication. However, our understanding of the associated molecular mechanisms remains limited. Here, we show that RSV infection blocks cholesterol transport from lysosomes to the endoplasmic reticulum by downregulating the activity of lysosomal acid lipase, activates the SREBP2-LDLR axis, and promotes uptake and accumulation of exogenous cholesterol in lysosomes. High cholesterol levels impair the VAP-A-binding activity of ORP1L and promote the recruitment of dynein-dynactin, PLEKHM1, or HOPS VPS39 to Rab7-RILP, thereby facilitating minus-end transport of autophagosomes and autolysosome formation. Acidification inhibition and dysfunction of cholesterol-rich lysosomes impair autophagy flux by inhibiting autolysosome degradation, which promotes the accumulation of RSV fusion protein. RSV-F storage is nearly abolished after cholesterol depletion or knockdown of LDLR. Most importantly, the knockout of LDLR effectively inhibits RSV infection in vivo. These findings elucidate the molecular mechanism of how RSV co-regulates lysosomal cholesterol reprogramming and autophagy and reveal LDLR as a novel target for anti-RSV drug development.
(© 2024. The Author(s).)
Databáze: MEDLINE
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