IRG1 catalyzed energy metabolite itaconic acid restrains type I interferon-dependent immune responses by alkylation of TBK1

Perturbation of energy metabolism is an essential feature during infection and inflammation. TANK-binding kinase 1 (TBK1) is crucial for initiating the innate immune response against viral infection, although aberrant and ongoing TBK1 activation induces excessive production of type I interferons (IFN-I). Nonetheless, the mechanisms whereby energy metabolism controls TBK1 activation remain unclear. Here, we elucidate a mechanism linking energy metabolism to the inhibition of TBK1-induced IFN-I responses via the immune response gene 1 (IRG1)-itaconic acid axis. Mechanistically, itaconic acid and its derivatives alkylated TBK1 at Cys605, thereby disrupting TBK1 dimerization and rapid activation. IRG1, the enzyme that catalyzes itaconic acid production, is upregulated during late-phase viral infection and acts as a feedback regulator to restrain TBK1 activity. We developed itaconic acid-based compounds ITA-5/ITA-9 as alternative TBK1 inhibitors. ITA-5/ITA-9 effectively limited excess IFN-I-mediated hyperinflammation. These findings provide a promising therapeutic strategy for treating diseases mediated by aberrant TBK1 activation.

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Journal
Cell Reports
Published
2025-09-27
DOI
https://doi.org/10.1016/j.celrep.2025.116336
Citations
2
Primary Topic
interferon and immune responses
Type
article
Field-Weighted Citation Impact
1.59
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article

IRG1 catalyzed energy metabolite itaconic acid restrains type I interferon-dependent immune responses by alkylation of TBK1

Yanyang Qin, Jialin Gao, Huan Zhou, Li Chai et al.
2 citations
Cell Reports
interferon and immune responses
1.59
article

IRG1 catalyzed energy metabolite itaconic acid restrains type I interferon-dependent immune responses by alkylation of TBK1

Yanyang Qin, Jialin Gao, Huan Zhou, Li Chai, Chengjiang Gao, Tao Wu, Mutian Jia, Meng Nie, Meng Wu, Jie Du, Dongwei Kang, Jihui Jia, Wei Zhao, Xuefeng Wang, Chaoqun Li, Yang Liu, Hemin Sun, Rong Gong, Jiangkun Xiong, Dongmei Hu, Zhiyuan Zhao
article en
2 citations

Abstract

Perturbation of energy metabolism is an essential feature during infection and inflammation. TANK-binding kinase 1 (TBK1) is crucial for initiating the innate immune response against viral infection, although aberrant and ongoing TBK1 activation induces excessive production of type I interferons (IFN-I). Nonetheless, the mechanisms whereby energy metabolism controls TBK1 activation remain unclear. Here, we elucidate a mechanism linking energy metabolism to the inhibition of TBK1-induced IFN-I responses via the immune response gene 1 (IRG1)-itaconic acid axis. Mechanistically, itaconic acid and its derivatives alkylated TBK1 at Cys605, thereby disrupting TBK1 dimerization and rapid activation. IRG1, the enzyme that catalyzes itaconic acid production, is upregulated during late-phase viral infection and acts as a feedback regulator to restrain TBK1 activity. We developed itaconic acid-based compounds ITA-5/ITA-9 as alternative TBK1 inhibitors. ITA-5/ITA-9 effectively limited excess IFN-I-mediated hyperinflammation. These findings provide a promising therapeutic strategy for treating diseases mediated by aberrant TBK1 activation.

Cell ReportsVol. 44(10)
Wannan Medical College (CN), Shandong University (CN), Bengbu Medical College (CN), Capital Medical University (CN), Anhui Medical University (CN), First Affiliated Hospital of Anhui Medical University (CN), First Affiliated Hospital of Bengbu Medical College (CN), Qilu Hospital of Shandong University (CN), First Affiliated Hospital of Wannan Medical College (CN)
Openalex Percentile: Top 14%
interferon and immune responses
1.59
DOIOpen Access PDFOpenAlex
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