Citrullination of VDAC3 by PAD2 restricts mitochondrial metabolism and suppresses macrophage reprogramming in sepsis.
8 affiliations
- 1Department of Surgery, University of Michigan Health System, Ann Arbor, United States.
- 2Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
- 3Department of Surgery, Division of Surgical Science, University of Virginia, Charlottesville, United States.
- 4Neuroscience Institute and Department of Neurosurgery, Baylor Scott & White Health, Temple, Texas, United States.
- 5Metware Biotechnology Inc., Woburn, MA, United States.
- 6Department of Neurosurgery, Baylor College of Medicine, Temple, Texas, United States.
- 7Texas A&M University Colleges of Medicine and Pharmacy, College Station, United States.
- 8Cancer Research Center and Department of Internal Medicine, Dell Medical School, the University of Texas at Austin, Austin, Texas, United States.
Abstract
Sepsis is a life-threatening inflammatory disorder characterized by immune dysregulation and organ failure, and while peptidylarginine deiminase-2 (PAD2) regulates immune responses via citrullination, its role in immunometabolism remains unclear. Here we identify a PAD2-dependent mechanism that impairs mitochondrial glutamine metabolism and macrophage polarization during sepsis. Through single-cell RNA sequencing of bronchoalveolar lavage fluid from septic mice, we found that Pad2 -/- promotes M2 macrophage polarization, reduces lung injury, and improves survival. Using mass spectrometry-based citrullinomics, we identified voltage-dependent anion channel-3 (VDAC3) as a PAD2 substrate, and further demonstrated that PAD2-mediated citrullination at residue R252 suppresses glutamine transport and α-ketoglutarate (α-KG) production, thereby impairing oxidative phosphorylation (OXPHOS) and M2 reprogramming. Notably, substitution of R252 with alanine recapitulated Pad2 -/-phenotypes, and consistent with this, Pad2 -/- mice exhibited enhanced OXPHOS, attenuated inflammation, and improved outcomes in a Pseudomonas aeruginosa-induced model of sepsis and lung injury. Collectively, these findings establish the PAD2-VDAC3-glutamine axis as a key immunometabolic checkpoint that links post-translational modification to mitochondrial metabolism and macrophage function, suggesting that targeting this pathway may offer a promising strategy to restore immune balance in sepsis.
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BibTeX
@article{shao2026citrullination,
title = {{Citrullination of VDAC3 by PAD2 restricts mitochondrial metabolism and suppresses macrophage reprogramming in sepsis.}},
author = {Liujiazi Shao and Chao Quan and Tao Dong and Yuchen Chen and Xin Yu and Wenlu Ouyang and Dan Qi and Jeffrey Chu and Erxi Wu and Zequan Yang and Jianjie Ma and Yongqing Li},
journal = {International journal of biological sciences},
year = {2026},
month = sep,
doi = {10.7150/ijbs.126368},
url = {https://europepmc.org/article/MED/42910200},
note = {CC BY},
}
RIS
TY - JOUR
TI - Citrullination of VDAC3 by PAD2 restricts mitochondrial metabolism and suppresses macrophage reprogramming in sepsis.
AU - Liujiazi Shao
AU - Chao Quan
AU - Tao Dong
AU - Yuchen Chen
AU - Xin Yu
AU - Wenlu Ouyang
AU - Dan Qi
AU - Jeffrey Chu
AU - Erxi Wu
AU - Zequan Yang
AU - Jianjie Ma
AU - Yongqing Li
PY - 2026
DA - 2026/09/11
JO - International journal of biological sciences
DO - 10.7150/ijbs.126368
UR - https://europepmc.org/article/MED/42910200
AB - Sepsis is a life-threatening inflammatory disorder characterized by immune dysregulation and organ failure, and while peptidylarginine deiminase-2 (PAD2) regulates immune responses via citrullination, its role in immunometabolism remains unclear. Here we identify a PAD2-dependent mechanism that impairs mitochondrial glutamine metabolism and macrophage polarization during sepsis. Through single-cell RNA sequencing of bronchoalveolar lavage fluid from septic mice, we found that Pad2 -/- promotes M2 macrophage polarization, reduces lung injury, and improves survival. Using mass spectrometry-based citrullinomics, we identified voltage-dependent anion channel-3 (VDAC3) as a PAD2 substrate, and further demonstrated that PAD2-mediated citrullination at residue R252 suppresses glutamine transport and α-ketoglutarate (α-KG) production, thereby impairing oxidative phosphorylation (OXPHOS) and M2 reprogramming. Notably, substitution of R252 with alanine recapitulated Pad2 -/-phenotypes, and consistent with this, Pad2 -/- mice exhibited enhanced OXPHOS, attenuated inflammation, and improved outcomes in a Pseudomonas aeruginosa-induced model of sepsis and lung injury. Collectively, these findings establish the PAD2-VDAC3-glutamine axis as a key immunometabolic checkpoint that links post-translational modification to mitochondrial metabolism and macrophage function, suggesting that targeting this pathway may offer a promising strategy to restore immune balance in sepsis.
SN - 1449-2288
ER -