Autoimmune disease risk gene ANKRD55 promotes TH17 effector function through metabolic modulation
Name
jem_20250185.pdf
Description
Published version
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8.95 MB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
Xu, Jinjin
Kong, Lingjia
Creasey, Elizabeth A
Rath, Sneha
Deng, Lei
Avila-Pacheco, Julian
Li, Chenhao
Oliver, Blayne A
Dao, Tyler T
Shih, Angela R
Date Issued
November 3, 2025
Journal
Journal of Experimental Medicine
Publisher
Rockefeller University Press
Citation
Jinjin Xu, Lingjia Kong, Elizabeth A. Creasey, Sneha Rath, Lei Deng, Julian Avila-Pacheco, Chenhao Li, Blayne A. Oliver, Tyler T. Dao, Angela R. Shih, Mark J. Daly, Alex K. Shalek, Clary B. Clish, Daniel B. Graham, Jacques Deguine, Ramnik J. Xavier; Autoimmune disease risk gene ANKRD55 promotes TH17 effector function through metabolic modulation. J Exp Med 3 November 2025; 222 (11): e20250185.
Version
Final published version
Abstract
Genome-wide association studies (GWAS) have linked the locus encoding ankyrin repeat domain 55 (ANKRD55) with numerous autoimmune diseases; however, its biological function and role in inflammation are unclear. Here, we demonstrate that Ankrd55-deficient mice are protected from T cell–mediated colitis but are more susceptible to Citrobacter rodentium infection. Mechanistically, Ankrd55 deletion impairs CD4+ T cell proliferation and reduces effector cytokine production in T helper 17 (TH17) cells in a cell-intrinsic manner. ANKRD55 is associated with mitochondria, and its loss is associated with impaired mitochondrial respiration and activation of the LKB1 pathway. Consistently, IL-17 production can be rescued by the deletion of LKB1 in Ankrd55-deficient T cells. Altogether, our study implicates the protein ANKRD55 as a functional modulator of T cell metabolism that directly impacts TH17 responses, highlighting it as a potential target across multiple autoimmune diseases.
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DOI of Published Version
https://doi.org/10.1084/jem.20250185
