UMMS Affiliation

Division of Infectious Diseases and Immunology, Department of Medicine

Publication Date

2019-05-29

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Biochemical Phenomena, Metabolism, and Nutrition | Genetic Phenomena | Hemic and Immune Systems | Immunity | Immunology of Infectious Disease | Immunopathology | Virus Diseases | Viruses

Abstract

The mitochondrial antiviral signaling protein (MAVS) orchestrates host antiviral innate immune response to RNA virus infection. However, how MAVS signaling is controlled to eradicate virus while preventing self-destructive inflammation remains obscure. Here, we show that protein geranylgeranylation, a posttranslational lipid modification of proteins, limits MAVS-mediated immune signaling by targeting Rho family small guanosine triphosphatase Rac1 into the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) at the mitochondria-ER junction. Protein geranylgeranylation and subsequent palmitoylation promote Rac1 translocation into MAMs upon viral infection. MAM-localized Rac1 limits MAVS' interaction with E3 ligase Trim31 and hence inhibits MAVS ubiquitination, aggregation, and activation. Rac1 also facilitates the recruitment of caspase-8 and cFLIPL to the MAVS signalosome and the subsequent cleavage of Ripk1 that terminates MAVS signaling. Consistently, mice with myeloid deficiency of protein geranylgeranylation showed improved survival upon influenza A virus infection. Our work revealed a critical role of protein geranylgeranylation in regulating antiviral innate immune response.

Keywords

innate immune response, antiviral, signaling protein, protein geranylgeranylation

Rights and Permissions

Copyright © 2019. The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

DOI of Published Version

10.1126/sciadv.aav7999

Source

Sci Adv. 2019 May 29;5(5):eaav7999. doi: 10.1126/sciadv.aav7999. eCollection 2019 May. Link to article on publisher's site

Journal/Book/Conference Title

Science advances

Comments

Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to Article in PubMed

PubMed ID

31149635

Creative Commons License

Creative Commons Attribution-Noncommercial 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License

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