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

Lifeng Chen, Jingjing Zhang, Weibin Xu, Jiayi Chen, Yujun Tang, Si Xiong, Yaolan Li, Hong Zhang (), Manmei Li () and Zhong Liu ()
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Lifeng Chen: Jinan University
Jingjing Zhang: Jinan University
Weibin Xu: Jinan University
Jiayi Chen: Jinan University
Yujun Tang: Jinan University
Si Xiong: Jinan University
Yaolan Li: Jinan University
Hong Zhang: Jinan University
Manmei Li: Jinan University
Zhong Liu: Jinan University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-50711-4

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