The m 6 A reader IMP2 directs autoimmune inflammation through an IL-17- and TNFα-dependent C/EBP transcription factor axis

• Published in: Science immunology Vol. 6; no. 61
• Main Authors: Bechara, Rami, Amatya, Nilesh, Bailey, Rachel D, Li, Yang, Aggor, Felix E Y, Li, De-Dong, Jawale, Chetan V, Coleman, Bianca M, Dai, Ning, Gokhale, Nandan S, Taylor, Tiffany C, Horner, Stacy M, Poholek, Amanda C, Bansal, Anita, Biswas, Partha S, Gaffen, Sarah L
• Format: Journal Article
• Language: English
• Published: United States 29.07.2021
• Subjects: Adenosine - analogs & derivatives; Adenosine - immunology; Animals; Autoimmunity - immunology; CCAAT-Enhancer-Binding Proteins - genetics; CCAAT-Enhancer-Binding Proteins - immunology; Cell Line; Female; Humans; Inflammation - immunology; Interleukin-17 - genetics; Interleukin-17 - immunology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; RNA-Binding Proteins - genetics; RNA-Binding Proteins - immunology; Tumor Necrosis Factor-alpha - immunology
• ISSN: 2470-9468
• DOI: 10.1126/sciimmunol.abd1287

Excessive cytokine activity underlies many autoimmune conditions, particularly through the interleukin-17 (IL-17) and tumor necrosis factor-α (TNFα) signaling axis. Both cytokines activate nuclear factor κB, but appropriate induction of downstream effector genes requires coordinated activation of other transcription factors, notably, CCAAT/enhancer binding proteins (C/EBPs). Here, we demonstrate the unexpected involvement of a posttranscriptional "epitranscriptomic" mRNA modification [N6-methyladenosine (m A)] in regulating C/EBPβ and C/EBPδ in response to IL-17A, as well as IL-17F and TNFα. Prompted by the observation that C/EBPβ/δ-encoding transcripts contain m A consensus sites, we show that and mRNAs are subject to m A modification. Induction of C/EBPs is enhanced by an m A methylase "writer" and suppressed by a demethylase "eraser." The only m A "reader" found to be involved in this pathway was IGF2BP2 (IMP2), and IMP2 occupancy of and mRNA was enhanced by m A modification. IMP2 facilitated IL-17-mediated mRNA stabilization and promoted translation of C/EBPβ/δ in response to IL-17A, IL-17F, and TNFα. RNA sequencing revealed transcriptome-wide IL-17-induced transcripts that are IMP2 influenced, and RNA immunoprecipitation sequencing identified the subset of mRNAs that are directly occupied by IMP2, which included and Lipocalin-2 ( ), a hallmark of autoimmune kidney injury, was strongly dependent on IL-17, IMP2, and C/EBPβ/δ. mice were resistant to autoantibody-induced glomerulonephritis (AGN), showing impaired renal expression of C/EBPs and Moreover, IMP2 deletion initiated only after AGN onset ameliorated disease. Thus, posttranscriptional regulation of C/EBPs through m A/IMP2 represents a previously unidentified paradigm of cytokine-driven autoimmune inflammation.