Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Molecular evolution of IRG1 shapes itaconate production in metazoans and alleviates the “double-edged dilemma” of innate immune defense

View ORCID ProfileRichard V. Szeligowski, Francois Miros, Andres Saez, Marisa DeCiucis, Gunter P. Wagner, View ORCID ProfileHongying Shen
doi: https://doi.org/10.1101/2022.06.17.496652
Richard V. Szeligowski
1Department of Cellular and Molecular Physiology, Yale University School of Medicine, CT, USA
2Systems Biology Institute, Yale University, CT, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Richard V. Szeligowski
  • For correspondence: richard.szeligowski@yale.edu
Francois Miros
1Department of Cellular and Molecular Physiology, Yale University School of Medicine, CT, USA
2Systems Biology Institute, Yale University, CT, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Andres Saez
1Department of Cellular and Molecular Physiology, Yale University School of Medicine, CT, USA
2Systems Biology Institute, Yale University, CT, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marisa DeCiucis
1Department of Cellular and Molecular Physiology, Yale University School of Medicine, CT, USA
2Systems Biology Institute, Yale University, CT, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gunter P. Wagner
2Systems Biology Institute, Yale University, CT, USA
3Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hongying Shen
1Department of Cellular and Molecular Physiology, Yale University School of Medicine, CT, USA
2Systems Biology Institute, Yale University, CT, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Hongying Shen
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Preview PDF
Loading

Abstract

Itaconate is an innate immune metabolite specifically produced in stimulated immune cells via the decarboxylation of the TCA cycle intermediate cis-aconitate. Due to its inhibition of succinate-related metabolic processes, itaconate exhibits antimicrobial properties at the expense of potentially disrupting the hosts own central energy metabolism, a double-edged dilemma of immunometabolism. To understand the evolutionary logic of itaconate biosynthesis, we investigate the evolutionary trajectory of the Irg1 gene, which codes for the itaconate-producing enzyme cis-aconitate decarboxylase (CAD). Phylogenetic analysis reveals a putative independent acquisition of metazoan and fungal Irg1 from prokaryotic sources. The metazoan Irg1 underwent duplication in vertebrates and a subsequent loss of one paralog in mammals, a process that removes the mitochondrial targeting sequences (MTS) and relocates CAD outside of the mitochondrial matrix thus preventing a direct inhibition of energy metabolism. Experiments in the most diverged metazoan species that are known to contain Irg1, oysters and amphioxus, reveal that the expression of primitive Irg1 genes is induced by innate immune stimulants in invertebrates and basal chordates, suggesting an already specialized role of itaconate production for innate immune defense in early bilaterians. Our combined in silico and experimental analysis of Irg1 highlights that a trend of tightened transcriptional regulation and sequence-level change optimizes itaconate biosynthesis for innate immunity, a mechanism that may be broadly utilized to resolve other types of double-edged dilemmas in immunometabolism.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Back to top
PreviousNext
Posted June 21, 2022.
Download PDF
Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Molecular evolution of IRG1 shapes itaconate production in metazoans and alleviates the “double-edged dilemma” of innate immune defense
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Molecular evolution of IRG1 shapes itaconate production in metazoans and alleviates the “double-edged dilemma” of innate immune defense
Richard V. Szeligowski, Francois Miros, Andres Saez, Marisa DeCiucis, Gunter P. Wagner, Hongying Shen
bioRxiv 2022.06.17.496652; doi: https://doi.org/10.1101/2022.06.17.496652
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
Molecular evolution of IRG1 shapes itaconate production in metazoans and alleviates the “double-edged dilemma” of innate immune defense
Richard V. Szeligowski, Francois Miros, Andres Saez, Marisa DeCiucis, Gunter P. Wagner, Hongying Shen
bioRxiv 2022.06.17.496652; doi: https://doi.org/10.1101/2022.06.17.496652

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Evolutionary Biology
Subject Areas
All Articles
  • Animal Behavior and Cognition (3586)
  • Biochemistry (7545)
  • Bioengineering (5495)
  • Bioinformatics (20732)
  • Biophysics (10294)
  • Cancer Biology (7951)
  • Cell Biology (11611)
  • Clinical Trials (138)
  • Developmental Biology (6586)
  • Ecology (10168)
  • Epidemiology (2065)
  • Evolutionary Biology (13580)
  • Genetics (9521)
  • Genomics (12817)
  • Immunology (7906)
  • Microbiology (19503)
  • Molecular Biology (7641)
  • Neuroscience (41982)
  • Paleontology (307)
  • Pathology (1254)
  • Pharmacology and Toxicology (2192)
  • Physiology (3259)
  • Plant Biology (7025)
  • Scientific Communication and Education (1294)
  • Synthetic Biology (1947)
  • Systems Biology (5419)
  • Zoology (1113)