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

Cellular & Molecular Immunology (2024)Cite this article

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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.

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Fig. 1: Decreased expression of spliceosomal RBM25 in inflammatory macrophages promotes arthritis pathogenesis.
Fig. 2: Macrophage-specific deficiency of RBM25 enhances IL-1β production in vitro and in vivo.
Fig. 3: RBM25 controls metabolic rewiring during proinflammatory macrophage activation.
Fig. 4: RBM25-mediated transcription suppression depends on the glycolysis-epigenetics axis.
Fig. 5: Identification of Acly pre-mRNA as the direct splicing RNA target of RBM25.
Fig. 6: The acquisition of Aclyl short isoform by 14th exon skipping supports immunostimulatory macrophage function.
Fig. 7: Aclyl activity is influenced by protein lactylation at K918/995 through P300.
Fig. 8: RBM25 cKO mice develop aging-associated inflammation in multiple organs and can be ameliorated by Acly inhibitor.

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Data availability

RNA sequencing, CUT&Tag sequencing and RIP sequencing raw data were deposited in the NCBI Gene Expression Omnibus database under the accession numbers GSE240157, GSE240158, GSE272304, GSE240159, and GSE240188, respectively.

References

  1. Tardito S, Martinelli G, Soldano S, Paolino S, Pacini G, Patane M, et al. Macrophage M1/M2 polarization and rheumatoid arthritis: A systematic review. Autoimmun Rev. 2019;18:102397.

    Article  PubMed  CAS  Google Scholar 

  2. Udalova IA, Mantovani A, Feldmann M. Macrophage heterogeneity in the context of rheumatoid arthritis. Nat Rev Rheumatol. 2016;12:472–85.

    Article  PubMed  CAS  Google Scholar 

  3. Zhang F, Wei K, Slowikowski K, Fonseka CY, Rao DA, Kelly S, et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat Immunol. 2019;20:928–42.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Abramson SB, Amin A. Blocking the effects of IL-1 in rheumatoid arthritis protects bone and cartilage. Rheumatology. 2002;41:972–80.

    Article  PubMed  CAS  Google Scholar 

  5. Strand V, Kavanaugh AF. The role of interleukin-1 in bone resorption in rheumatoid arthritis. Rheumatology. 2004;43:iii10–iii16.

    Article  PubMed  Google Scholar 

  6. Liu J, Cao X. RBP-RNA interactions in the control of autoimmunity and autoinflammation. Cell Res. 2023;33:97–115.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Wu H, Gonzalez Villalobos R, Yao X, Reilly D, Chen T, Rankin M, et al. Mapping the single-cell transcriptomic response of murine diabetic kidney disease to therapies. Cell Metab. 2022;34:1064–78.e6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Hasler R, Kerick M, Mah N, Hultschig C, Richter G, Bretz F, et al. Alterations of pre-mRNA splicing in human inflammatory bowel disease. Eur J Cell Biol. 2011;90:603–11.

    Article  PubMed  Google Scholar 

  9. Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF, Goel G, et al. Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature. 2013;496:238–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Palsson-McDermott EM, Curtis AM, Goel G, Lauterbach MA, Sheedy FJ, Gleeson LE, et al. Pyruvate kinase M2 regulates Hif-1alpha activity and IL-1beta induction and is a critical determinant of the warburg effect in LPS-activated macrophages. Cell Metab. 2015;21:65–80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumor growth. Nature. 2008;452:230–3.

    Article  PubMed  CAS  Google Scholar 

  12. Israelsen WJ, Dayton TL, Davidson SM, Fiske BP, Hosios AM, Bellinger G, et al. PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell. 2013;155:397–409.

    Article  PubMed  CAS  Google Scholar 

  13. Ester C, Uetz P. The FF domains of yeast U1 snRNP protein Prp40 mediate interactions with Luc7 and Snu71. BMC Biochem. 2008;9:29.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Bishof I, Dammer EB, Duong DM, Kundinger SR, Gearing M, Lah JJ, et al. RNA-binding proteins with basic-acidic dipeptide (BAD) domains self-assemble and aggregate in Alzheimer’s disease. J Biol Chem. 2018;293:11047–66.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Zanoni P, Panteloglou G, Othman A, Haas JT, Meier R, Rimbert A, et al. Posttranscriptional Regulation of the Human LDL Receptor by the U2-Spliceosome. Circ Res. 2022;130:80–95.

    Article  PubMed  CAS  Google Scholar 

  16. Bramlett C, Eerdeng J, Jiang D, Lee Y, Garcia I, Vergel-Rodriguez M, et al. RNA splicing factor Rbm25 underlies heterogeneous preleukemic clonal expansion in mice. Blood. 2023;141:2961–72.

    PubMed  PubMed Central  CAS  Google Scholar 

  17. Woetzel D, Huber R, Kupfer P, Pohlers D, Pfaff M, Driesch D, et al. Identification of rheumatoid arthritis and osteoarthritis patients by transcriptome-based rule set generation. Arthritis Res Ther. 2014;16:R84.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Garcia S, Forteza J, Lopez-Otin C, Gomez-Reino JJ, Gonzalez A, Conde C. Matrix metalloproteinase-8 deficiency increases joint inflammation and bone erosion in the K/BxN serum-transfer arthritis model. Arthritis Res Ther. 2010;12:R224.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Yan M, Komatsu N, Muro R, Huynh NC, Tomofuji Y, Okada Y, et al. ETS1 governs pathological tissue-remodeling programs in disease-associated fibroblasts. Nat Immunol. 2022;23:1330–41.

    Article  PubMed  CAS  Google Scholar 

  20. Cuartero S, Weiss FD, Dharmalingam G, Guo Y, Ing-Simmons E, Masella S, et al. Control of inducible gene expression links cohesin to hematopoietic progenitor self-renewal and differentiation. Nat Immunol. 2018;19:932–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Soldi M, Mari T, Nicosia L, Musiani D, Sigismondo G, Cuomo A, et al. Chromatin proteomics reveals novel combinatorial histone modification signatures that mark distinct subpopulations of macrophage enhancers. Nucleic Acids Res. 2017;45:12195–213.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Nicodeme E, Jeffrey KL, Schaefer U, Beinke S, Dewell S, Chung CW, et al. Suppression of inflammation by a synthetic histone mimic. Nature. 2010;468:1119–23.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Brand DD, Latham KA, Rosloniec EF. Collagen-induced arthritis. Nat Protoc. 2007;2:1269–75.

    Article  PubMed  CAS  Google Scholar 

  24. Watson WC, Townes AS. Genetic susceptibility to murine collagen II autoimmune arthritis. Proposed relationship to the IgG2 autoantibody subclass response, complement C5, major histocompatibility complex (MHC) and non-MHC loci. J Exp Med. 1985;162:1878–91.

    Article  PubMed  CAS  Google Scholar 

  25. Zhang B, Zhang Y, Xiong L, Li Y, Zhang Y, Zhao J, et al. CD127 imprints functional heterogeneity to diversify monocyte responses in inflammatory diseases. J Exp Med. 2022;219:e20211191.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Mangan MSJ, Olhava EJ, Roush WR, Seidel HM, Glick GD, Latz E. Targeting the NLRP3 inflammasome in inflammatory diseases. Nat Rev Drug Discov. 2018;17:588–606.

    Article  PubMed  CAS  Google Scholar 

  27. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440:237–41.

    Article  PubMed  CAS  Google Scholar 

  28. Guo H, Ting JP. Inflammasome Assays In Vitro and in Mouse Models. Curr Protoc Immunol. 2020;131:e107.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Xiao R, Chen JY, Liang Z, Luo D, Chen G, Lu ZJ, et al. Pervasive chromatin-RNA binding protein interactions enable RNA-based regulation of transcription. Cell. 2019;178:107–21.e18.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Lin J, He Y, Chen J, Zeng Z, Yang B, Ou Q. A critical role of transcription factor YY1 in rheumatoid arthritis by regulation of interleukin-6. J Autoimmun. 2017;77:67–75.

    Article  PubMed  CAS  Google Scholar 

  31. Russell DG, Huang L, VanderVen BC. Immunometabolism at the interface between macrophages and pathogens. Nat Rev Immunol. 2019;19:291–304.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. O’Neill LA, Pearce EJ. Immunometabolism governs dendritic cell and macrophage function. J Exp Med. 2016;213:15–23.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Shakespear MR, Iyer A, Cheng CY, Das Gupta K, Singhal A, Fairlie DP, et al. Lysine Deacetylases and Regulated Glycolysis in Macrophages. Trends Immunol. 2018;39:473–88.

    Article  PubMed  CAS  Google Scholar 

  34. Corcoran SE, O’Neill LA. HIF1alpha and metabolic reprogramming in inflammation. J Clin Invest. 2016;126:3699–707.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Carlson SM, Soulette CM, Yang Z, Elias JE, Brooks AN, Gozani O. RBM25 is a global splicing factor promoting inclusion of alternatively spliced exons and is itself regulated by lysine mono-methylation. J Biol Chem. 2017;292:13381–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Zhou A, Ou AC, Cho A, Benz EJ Jr, Huang SC. Novel splicing factor RBM25 modulates Bcl-x pre-mRNA 5’ splice site selection. Mol Cell Biol. 2008;28:5924–36.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Di Gioia M, Spreafico R, Springstead JR, Mendelson MM, Joehanes R, Levy D, et al. Endogenous oxidized phospholipids reprogram cellular metabolism and boost hyperinflammation. Nat Immunol. 2020;21:42–53.

    Article  PubMed  Google Scholar 

  38. Lauterbach MA, Hanke JE, Serefidou M, Mangan MSJ, Kolbe CC, Hess T, et al. Toll-like Receptor Signaling Rewires Macrophage Metabolism and Promotes Histone Acetylation via ATP-Citrate Lyase. Immunity. 2019;51:997–1011.e7.

    Article  PubMed  CAS  Google Scholar 

  39. Wan L, Yu W, Shen E, Sun W, Liu Y, Kong J, et al. SRSF6-regulated alternative splicing that promotes tumor progression offers a therapy target for colorectal cancer. Gut. 2019;68:118–29.

    Article  PubMed  CAS  Google Scholar 

  40. Kasowitz SD, Ma J, Anderson SJ, Leu NA, Xu Y, Gregory BD, et al. Nuclear m6A reader YTHDC1 regulates alternative polyadenylation and splicing during mouse oocyte development. PLoS Genet. 2018;14:e1007412.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Tong J, Wang X, Liu Y, Ren X, Wang A, Chen Z, et al. Pooled CRISPR screening identifies m(6)A as a positive regulator of macrophage activation. Sci Adv. 2021;7:eabd4742.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Zheng Q, Hou J, Zhou Y, Li Z, Cao X. The RNA helicase DDX46 inhibits innate immunity by entrapping m(6)A-demethylated antiviral transcripts in the nucleus. Nat Immunol. 2017;18:1094–103.

    Article  PubMed  CAS  Google Scholar 

  43. Pearce NJ, Yates JW, Berkhout TA, Jackson B, Tew D, Boyd H, et al. The role of ATP citrate-lyase in the metabolic regulation of plasma lipids. Hypolipidemic effects of SB-204990, a lactone prodrug of the potent ATP citrate-lyase inhibitor SB-201076. Biochem J. 1998;334:113–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Migita T, Narita T, Nomura K, Miyagi E, Inazuka F, Matsuura M, et al. ATP citrate lyase: activation and therapeutic implications in non-small cell lung cancer. Cancer Res. 2008;68:8547–54.

    Article  PubMed  CAS  Google Scholar 

  45. Wei J, Leit S, Kuai J, Therrien E, Rafi S, Harwood HJ Jr, et al. An allosteric mechanism for potent inhibition of human ATP-citrate lyase. Nature. 2019;568:566–70.

    Article  PubMed  CAS  Google Scholar 

  46. Bazilevsky GA, Affronti HC, Wei X, Campbell SL, Wellen KE, Marmorstein R. ATP-citrate lyase multimerization is required for coenzyme-A substrate binding and catalysis. J Biol Chem. 2019;294:7259–68.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Wang N, Wang W, Wang X, Mang G, Chen J, Yan X, et al. Histone Lactylation Boosts Reparative Gene Activation Post-Myocardial Infarction. Circ Res. 2022;131:893–908.

    Article  PubMed  CAS  Google Scholar 

  48. Fan M, Yang K, Wang X, Chen L, Gill PS, Ha T, et al. Lactate promotes endothelial-to-mesenchymal transition via Snail1 lactylation after myocardial infarction. Sci Adv. 2023;9:eadc9465.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Yan Y, Tao H, He J, Huang SY. The HDOCK server for integrated protein‒protein docking. Nat Protoc. 2020;15:1829–52.

    Article  PubMed  CAS  Google Scholar 

  50. Yan Y, Zhang D, Zhou P, Li B, Huang SY. HDOCK: a web server for protein‒protein and protein‒DNA/RNA docking based on a hybrid strategy. Nucleic Acids Res. 2017;45:W365–W73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Adasme MF, Linnemann KL, Bolz SN, Kaiser F, Salentin S, Haupt VJ, et al. PLIP 2021: expanding the scope of the protein‒ligand interaction profiler to DNA and RNA. Nucleic Acids Res. 2021;49:W530–W4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Vizioli MG, Liu T, Miller KN, Robertson NA, Gilroy K, Lagnado AB, et al. Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence. Genes Dev. 2020;34:428–45.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Meyers AK, Zhu X. The NLRP3 Inflammasome: Metabolic Regulation and Contribution to Inflammaging. Cells. 2020;9:1808.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Havens MA, Hastings ML. Splice-switching antisense oligonucleotides as therapeutic drugs. Nucleic Acids Res. 2016;44:6549–63.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Bauman JA, Li SD, Yang A, Huang L, Kole R. Anti-tumor activity of splice-switching oligonucleotides. Nucleic Acids Res. 2010;38:8348–56.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Gao G, Xie A, Huang SC, Zhou A, Zhang J, Herman AM, et al. Role of RBM25/LUC7L3 in abnormal cardiac sodium channel splicing regulation in human heart failure. Circulation. 2011;124:1124–31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Ge Y, Schuster MB, Pundhir S, Rapin N, Bagger FO, Sidiropoulos N, et al. The splicing factor RBM25 controls MYC activity in acute myeloid leukemia. Nat Commun. 2019;10:172.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Zhao B, Deng J, Ma M, Li N, Zhou J, Li X, et al. Environmentally relevant concentrations of 2,3,7,8-TCDD induced inhibition of multicellular alternative splicing and transcriptional dysregulation. Sci Total Environ. 2024;919:170892.

    Article  PubMed  CAS  Google Scholar 

  59. Kinyamu HK, Bennett BD, Bushel PR, Archer TK. Proteasome inhibition creates a chromatin landscape favorable to RNA Pol II processivity. J Biol Chem. 2020;295:1271–87.

    Article  PubMed  CAS  Google Scholar 

  60. Li J, Ahn JH, Wang GG. Understanding histone H3 lysine 36 methylation and its deregulation in disease. Cell Mol Life Sci. 2019;76:2899–916.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Duarte Lau F, Giugliano RP. Adenosine Triphosphate Citrate Lyase and Fatty Acid Synthesis Inhibition: A Narrative Review. JAMA Cardiol. 2023;8:879–87.

    Article  PubMed  Google Scholar 

  62. Ference BA, Ray KK, Catapano AL, Ference TB, Burgess S, Neff DR, et al. Mendelian Randomization Study of ACLY and Cardiovascular Disease. N. Engl J Med. 2019;380:1033–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Convertini P, Santarsiero A, Todisco S, Gilio M, Palazzo D, Pappalardo I, et al. ACLY as a modulator of liver cell functions and its role in Metabolic Dysfunction-Associated Steatohepatitis. J Transl Med. 2023;21:568.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Hochrein SM, Wu H, Eckstein M, Arrigoni L, Herman JS, Schumacher F, et al. The glucose transporter GLUT3 controls T helper 17 cell responses through glycolytic-epigenetic reprogramming. Cell Metab. 2022;34:516–32.e11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Soto-Heredero G, Gomez de Las Heras MM, Gabande-Rodriguez E, Oller J, Mittelbrunn M. Glycolysis-a key player in the inflammatory response. FEBS J. 2020;287:3350–69.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Langston PK, Nambu A, Jung J, Shibata M, Aksoylar HI, Lei J, et al. Glycerol phosphate shuttle enzyme GPD2 regulates macrophage inflammatory responses. Nat Immunol. 2019;20:1186–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Verberk SGS, van der Zande HJP, Baardman J, de Goede KE, Harber KJ, Keuning ED, et al. Myeloid ATP Citrate Lyase Regulates Macrophage Inflammatory Responses In Vitro Without Altering Inflammatory Disease Outcomes. Front Immunol. 2021;12:669920.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Birch J, Gil J. Senescence and the SASP: many therapeutic avenues. Genes Dev. 2020;34:1565–76.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Lu Y, Sun Q, Guan Q, Zhang Z, He Q, He J, et al. The XOR-IDH3alpha axis controls macrophage polarization in hepatocellular carcinoma. J Hepatol. 2023;79:1172–84.

    Article  PubMed  CAS  Google Scholar 

  70. Liu Y, You Y, Lu Z, Yang J, Li P, Liu L, et al. N (6)-methyladenosine RNA modification-mediated cellular metabolism rewiring inhibits viral replication. Science. 2019;365:1171–6.

    Article  PubMed  CAS  Google Scholar 

  71. David CJ, Chen M, Assanah M, Canoll P, Manley JL. HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature. 2010;463:364–8.

    Article  PubMed  CAS  Google Scholar 

  72. Xiong J, He J, Zhu J, Pan J, Liao W, Ye H, et al. Lactylation-driven METTL3-mediated RNA m(6)A modification promotes immunosuppression of tumor-infiltrating myeloid cells. Mol Cell. 2022;82:1660–77.e10.

    Article  PubMed  CAS  Google Scholar 

  73. Yang K, Fan M, Wang X, Xu J, Wang Y, Tu F, et al. Lactate promotes macrophage HMGB1 lactylation, acetylation, and exosomal release in polymicrobial sepsis. Cell Death Differ. 2022;29:133–46.

    Article  PubMed  CAS  Google Scholar 

  74. Chen L, Huang L, Gu Y, Cang W, Sun P, Xiang Y. Lactate-Lactylation Hands between Metabolic Reprogramming and Immunosuppression. Int J Mol Sci. 2022;23:11943.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Verschueren KHG, Blanchet C, Felix J, Dansercoer A, De Vos D, Bloch Y, et al. Structure of ATP citrate lyase and the origin of citrate synthase in the Krebs cycle. Nature. 2019;568:571–5.

    Article  PubMed  CAS  Google Scholar 

  76. Chen X, Birey F, Li MY, Revah O, Levy R, Thete MV, et al. Antisense oligonucleotide therapeutic approach for Timothy syndrome. Nature. 2024;628:818–25.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Ma WK, Voss DM, Scharner J, Costa ASH, Lin KT, Jeon HY, et al. ASO-based PKM splice-switching therapy inhibits hepatocellular carcinoma growth. Cancer Res. 2022;82:900–15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Li JD, Taipale M, Blencowe BJ. Efficient, specific, and combinatorial control of endogenous exon splicing with dCasRx-RBM25. Mol Cell. 2024;84:2573–89.e5.

    Article  PubMed  CAS  Google Scholar 

  79. Zhang Y, Gao Y, Jiang Y, Ding Y, Chen H, Xiang Y, et al. Histone demethylase KDM5B licenses macrophage-mediated inflammatory responses by repressing Nfkbia transcription. Cell Death Differ. 2023;30:1279–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Xia M, Liu J, Wu X, Liu S, Li G, Han C, et al. Histone methyltransferase Ash1l suppresses interleukin-6 production and inflammatory autoimmune diseases by inducing the ubiquitin-editing enzyme A20. Immunity. 2013;39:470–81.

    Article  PubMed  CAS  Google Scholar 

  81. Liu X, Zhang P, Zhang Y, Wang Z, Xu S, Li Y, et al. Glycolipid iGb3 feedback amplifies innate immune responses via CD1d reverse signaling. Cell Res. 2019;29:42–53.

    Article  PubMed  CAS  Google Scholar 

  82. Wang D, Zhang Y, Xu X, Wu J, Peng Y, Li J, et al. YAP promotes the activation of NLRP3 inflammasome by blocking K27-linked polyubiquitination of NLRP3. Nat Commun. 2021;12:2674.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Liu X, Zhan Z, Li D, Xu L, Ma F, Zhang P, et al. Intracellular MHC class II molecules promote TLR-triggered innate immune responses by maintaining activation of the kinase Btk. Nat Immunol. 2011;12:416–24.

    Article  PubMed  CAS  Google Scholar 

  84. Huai W, Liu X, Wang C, Zhang Y, Chen X, Chen X, et al. KAT8 selectively inhibits antiviral immunity by acetylating IRF3. J Exp Med. 2019;216:772–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Zhou Q, Zhang Y, Wang B, Zhou W, Bi Y, Huai W, et al. KDM2B promotes IL-6 production and inflammatory responses through Brg1-mediated chromatin remodeling. Cell Mol Immunol. 2020;17:834–42.

    Article  PubMed  CAS  Google Scholar 

  86. Zhang D, Tang Z, Huang H, Zhou G, Cui C, Weng Y, et al. Metabolic regulation of gene expression by histone lactylation. Nature. 2019;574:575–80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Stuart T, Butler A, Hoffman P, Hafemeister C, Papalexi E, Mauck WM 3rd, et al. Comprehensive Integration of Single-Cell Data. Cell. 2019;177:1888–902.e21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Ramirez-Carrozzi VR, Braas D, Bhatt DM, Cheng CS, Hong C, Doty KR, et al. A unifying model for the selective regulation of inducible transcription by CpG islands and nucleosome remodeling. Cell. 2009;138:114–28.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Lv D, Xu J, Qi M, Wang D, Xu W, Qiu L, et al. A strategy of screening and binding analysis of bioactive components from traditional Chinese medicine based on surface plasmon resonance biosensor. J Pharm Anal. 2022;12:500–8.

    Article  PubMed  Google Scholar 

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Funding

This work was supported by the National Key Research & Development Program of China (2023YFC2307302, 2019YFA0801502, 2023YFC2307001, 2023YFC2307002), the National Natural Science Foundation of China (82071790, 82070415, 82271797, 82341065, 82371825, 32400727, 82201955), the program of Shanghai outstanding academic leader in public health subject (GWVI-11.2-XD29), and the experimental animal program sponsored by the Science and Technology Commission of Shanghai Municipality (23141902300).

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Author notes

  1. These authors contributed equally: Yunkai Zhang, Ying Gao.

Authors and Affiliations

  1. Naval Medical Center, Naval Medical University, Shanghai, 200433, China

    Yunkai Zhang & Xiaomeng Ren

  2. National Key Laboratory of Immunity & Inflammation, Naval Medical University, Shanghai, 200433, China

    Yunkai Zhang, Yingying Ding, Huiying Chen, Bing Rui, Sheng Xu & Xingguang Liu

  3. Department of Pathogen Biology, Naval Medical University, Shanghai, 200433, China

    Yunkai Zhang, Yuyu Jiang, Yan Xiang, Xiaohui Wang, Zeting Wang, Yingying Ding, Huiying Chen, Bing Rui & Xingguang Liu

  4. Department of Rheumatology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China

    Ying Gao

  5. Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, 100730, China

    Yujia Wang

  6. Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

    Wanwan Huai

  7. Department of Otolaryngology, Changzheng Hospital, Naval Medical University, Shanghai, 200003, China

    Boyu Cai

  8. Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, 215123, China

    Feng Ma

  9. Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China

    Zhenzhen Zhan

  10. Shanghai Institute of Transplantation, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China

    Zhenzhen Zhan

  11. Key Laboratory of Biological Defense, Ministry of Education, Shanghai, 200433, China

    Xingguang Liu

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  1. Yunkai Zhang
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Contributions

Conceptualization: XL, ZZ, and YZ. Methodology: YZ, YG, YW, YJ, YX, BC, SX, and FM; investigation: YZ, YG, YW, YJ, YX, XW, ZW, YD, HC, BR, WH, and BC; visualization: YZ, YG, YJ, and YX; resources: SX, FM, and XR; funding acquisition: XL and ZZ; supervision: XL and ZZ; writing–original draft: YZ, XL, and ZZ; writing–review and editing: YZ, XL, and ZZ.

Corresponding authors

Correspondence to Zhenzhen Zhan or Xingguang Liu.

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The authors declare no competing interests.

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Zhang, Y., Gao, Y., Wang, Y. et al. RBM25 is required to restrain inflammation via ACLY RNA splicing-dependent metabolism rewiring. Cell Mol Immunol (2024). https://doi.org/10.1038/s41423-024-01212-3

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  • DOI: https://doi.org/10.1038/s41423-024-01212-3

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