Hepatitis E virus infection remodels the mature tRNAome in macrophages to orchestrate NLRP3 inflammasome response

Author:

Li Yunlong12ORCID,Zhang Ruyi2,Wang Yining2,Li Pengfei2,Li Yang2,Janssen Harry L. A.23,de Man Robert A.2ORCID,Peppelenbosch Maikel P.2ORCID,Ou Xumin45ORCID,Pan Qiuwei2ORCID

Affiliation:

1. Medical Faculty, Kunming University of Science and Technology, 450500 Kunming, Yunnan, China

2. Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, 3015GD Rotterdam, The Netherlands

3. Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, M5G 2C4 ON, Canada

4. Engineering Research Center of Southwest Animal Disease Prevention and Control Technology, Ministry of Education of the People’s Republic of China, 611130 Chengdu, Sichuan, China

5. Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, 611830 Chengdu, Sichuan, China

Abstract

Hepatitis E virus (HEV) infection has been shown to activate NOD-like receptor family pyrin domain–containing 3 (NLRP3) inflammasome in macrophages, a key mechanism of causing pathological inflammation, but the mechanisms regulating this response remain poorly understood. Here, we report that the mature tRNAome dynamically responds to HEV infection in macrophages. This directs IL-1β expression, the hallmark of NLRP3 inflammasome activation, at mRNA and protein levels. Conversely, pharmacological inhibition of inflammasome activation abrogates HEV-provoked tRNAome remodeling, revealing a reciprocal interaction between the mature tRNAome and the NLRP3 inflammasome response. Remodeling the tRNAome results in improved decoding of codons directing leucine- and proline synthesis, which are the major amino acid constituents of IL-1β protein, whereas genetic or functional interference with tRNAome-mediated leucine decoding impairs inflammasome activation. Finally, we demonstrated that the mature tRNAome also actively responds to lipopolysaccharide (a key component of gram-negative bacteria)-triggered inflammasome activation, but the response dynamics and mode of actions are distinct from that induced by HEV infection. Our findings thus reveal the mature tRNAome as a previously unrecognized but essential mediator of host response to pathogens and represent a unique target for developing anti-inflammatory therapeutics.

Funder

Dutch Research Council

National natural science foundation of China

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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