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primary topic: Itaconate mechanism of action and dissimilation in Mycobacterium tuberculosis

Itaconate mechanism of action and dissimilation in Mycobacterium tuberculosis
type: AcademicArticle
type: Article
abstract: Itaconate, an abundant metabolite produced by macrophages upon interferon-γ stimulation, possesses both antibacterial and immunomodulatory properties. Despite its crucial role in immunity and antimicrobial control, its mechanism of action and dissimilation are poorly understood. Here, we demonstrate that infection of mice with Mycobacterium tuberculosis increases itaconate levels in lung tissues. We also show that exposure to itaconate inhibits M. tuberculosis growth in vitro, in macrophages, and mice. We report that exposure to sodium itaconate (ITA) interferes with the central carbon metabolism of M. tuberculosis. In addition to the inhibition of isocitrate lyase (ICL), we demonstrate that itaconate inhibits aldolase and inosine monophosphate (IMP) dehydrogenase in a concentration-dependent manner. Previous studies have shown that Rv2498c from M. tuberculosis is the bona fide (S)-citramalyl-CoA lyase, but the remaining components of the pathway remain elusive. Here, we report that Rv2503c and Rv3272 possess itaconate:succinyl-CoA transferase activity, and Rv2499c and Rv3389c possess itaconyl-CoA hydratase activity. Relative to the parental and complemented strains, the ΔRv3389c strain of M. tuberculosis was attenuated for growth in itaconate-containing medium, in macrophages, mice, and guinea pigs. The attenuated phenotype of ΔRv3389c strain of M. tuberculosis is associated with a defect in the itaconate dissimilation and propionyl-CoA detoxification pathway. This study thus reveals that multiple metabolic enzymes are targeted by itaconate in M. tuberculosis. Furthermore, we have assigned the two remaining enzymes responsible for the degradation of itaconic acid into pyruvate and acetyl-CoA. Finally, we also demonstrate the importance of enzymes involved in the itaconate dissimilation pathway for M. tuberculosis pathogenesis.
date: 2025-01
volume: 122
issue: 4
author list: authors
type: EPrint
type: ArticleEPrint
is part of: repository

Proc. Natl. Acad. Sci. U. S. A.
type: Collection

Snigdha Tiwari
type: Person
given name: Snigdha
family name: Tiwari

Anil Koundal
type: Person
given name: Anil
family name: Koundal

Manisha Priya
type: Person
given name: Manisha
family name: Priya

Deepak Sharma
type: Person
given name: Deepak
family name: Sharma

Luiz Pedro Sorio de Carvalho
type: Person
given name: Luiz Pedro
family name: Sorio de Carvalho

Saqib Kidwai
type: Person
given name: Saqib
family name: Kidwai

Ramandeep Singh
type: Person
given name: Ramandeep
family name: Singh

Dinesh Mahajan
type: Person
given name: Dinesh
family name: Mahajan

Sonu Kumar Gupta
type: Person
given name: Sonu Kumar
family name: Gupta

Krishan Gopal Thakur
type: Person
given name: Krishan Gopal
family name: Thakur

Yashwant Kumar
type: Person
given name: Yashwant
family name: Kumar

Srajan Kapoor
type: Person
given name: Srajan
family name: Kapoor

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primary topic: Itaconate mechanism of action and dissimilation in Mycobacterium tuberculosis