2. Academic Validation
  3. RBM25 is required to restrain inflammation via ACLY RNA splicing-dependent metabolism rewiring

RBM25 is required to restrain inflammation via ACLY RNA splicing-dependent metabolism rewiring

  • Cell Mol Immunol. 2024 Nov;21(11):1231-1250. doi: 10.1038/s41423-024-01212-3.
Yunkai Zhang # 1 2 3,  Ying Gao # 4,  Yujia Wang 5,  Yuyu Jiang 3,  Yan Xiang 3,  Xiaohui Wang 3,  Zeting Wang 3,  Yingying Ding 2 3,  Huiying Chen 2 3,  Bing Rui 2 3,  Wanwan Huai 6,  Boyu Cai 7,  Xiaomeng Ren 1,  Feng Ma 8,  Sheng Xu 2,  Zhenzhen Zhan 9 10,  Xingguang Liu 11 12 13
Affiliations

Affiliations

  • 1 Naval Medical Center, Naval Medical University, Shanghai, 200433, China.
  • 2 National Key Laboratory of Immunity & Inflammation, Naval Medical University, Shanghai, 200433, China.
  • 3 Department of Pathogen Biology, Naval Medical University, Shanghai, 200433, China.
  • 4 Department of Rheumatology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China.
  • 5 Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, 100730, China.
  • 6 Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
  • 7 Department of Otolaryngology, Changzheng Hospital, Naval Medical University, Shanghai, 200003, China.
  • 8 Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, 215123, China.
  • 9 Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China. zhanzz2022@sjtu.edu.cn.
  • 10 Shanghai Institute of Transplantation, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. zhanzz2022@sjtu.edu.cn.
  • 11 National Key Laboratory of Immunity & Inflammation, Naval Medical University, Shanghai, 200433, China. liuxg@immunol.org.
  • 12 Department of Pathogen Biology, Naval Medical University, Shanghai, 200433, China. liuxg@immunol.org.
  • 13 Key Laboratory of Biological Defense, Ministry of Education, Shanghai, 200433, China. liuxg@immunol.org.
  • # Contributed equally.
PMID: 39251781 DOI: 10.1038/s41423-024-01212-3
Abstract

Spliceosome dysfunction and aberrant RNA splicing underline unresolved inflammation and immunopathogenesis. Here, we revealed the misregulation of mRNA splicing via the spliceosome in the pathogenesis of rheumatoid arthritis (RA). Among them, decreased expression of RNA binding motif protein 25 (RBM25) was identified as a major pathogenic factor in RA patients and experimental arthritis mice through increased proinflammatory mediator production and increased hyperinflammation in macrophages. Multiomics analyses of macrophages from RBM25-deficient mice revealed that the transcriptional enhancement of proinflammatory genes (including Il1b, Il6, and Cxcl10) was coupled with histone 3 lysine 9 acetylation (H3K9ac) and H3K27ac modifications as well as hypoxia inducible factor-1α (HIF-1α) activity. Furthermore, RBM25 directly bound to and mediated the 14th exon skipping of ATP Citrate Lyase (Acly) pre-mRNA, resulting in two distinct Acly isoforms, Acly Long (Acly L) and Acly Short (Acly S). In proinflammatory macrophages, Acly L was subjected to protein lactylation on lysine 918/995, whereas Acly S did not, which influenced its affinity for metabolic substrates and subsequent metabolic activity. RBM25 deficiency overwhelmingly increased the expression of the Acly S isoform, enhancing glycolysis and acetyl-CoA production for epigenetic remodeling, macrophage overactivation and tissue inflammatory injury. Finally, macrophage-specific deletion of RBM25 led to inflammaging, including spontaneous arthritis in various joints of mice and inflammation in multiple organs, which could be relieved by pharmacological inhibition of Acly. Overall, targeting the RBM25-Acly splicing axis represents a potential strategy for modulating macrophage responses in autoimmune arthritis and aging-associated inflammation.

Keywords

Acly; Histone acetylation; Inflammation; Metabolic reprogramming; RBM25; Splicing factor.

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