Control of antiviral innate immune response by protein geranylgeranylation

Sci Adv. 2019 May 29;5(5):eaav7999. doi: 10.1126/sciadv.aav7999. eCollection 2019 May.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Alkyl and Aryl Transferases / genetics
  • Alkyl and Aryl Transferases / metabolism
  • Animals
  • Endoplasmic Reticulum / immunology
  • Endoplasmic Reticulum / metabolism
  • Female
  • Humans
  • Immunity, Innate / physiology*
  • Macrophages, Alveolar / immunology
  • Macrophages, Alveolar / metabolism
  • Male
  • Mice, Knockout
  • Neuropeptides / genetics
  • Neuropeptides / metabolism*
  • Orthomyxoviridae Infections / immunology*
  • Orthomyxoviridae Infections / metabolism
  • Orthomyxoviridae Infections / mortality
  • Protein Prenylation / immunology*
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Tripartite Motif Proteins / metabolism
  • Ubiquitin-Protein Ligases / metabolism
  • rac GTP-Binding Proteins / genetics
  • rac GTP-Binding Proteins / metabolism
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • IPS-1 protein, mouse
  • Neuropeptides
  • Rac1 protein, mouse
  • Tripartite Motif Proteins
  • TRIM31 protein, mouse
  • Ubiquitin-Protein Ligases
  • Alkyl and Aryl Transferases
  • geranylgeranyltransferase type-I
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse
  • rac2 GTP-binding protein
  • rac GTP-Binding Proteins
  • rac1 GTP-Binding Protein