| First Author | Bechara R | Year | 2021 |
| Journal | Sci Immunol | Volume | 6 |
| Issue | 61 | PubMed ID | 34215679 |
| Mgi Jnum | J:322358 | Mgi Id | MGI:7258212 |
| Doi | 10.1126/sciimmunol.abd1287 | Citation | Bechara R, et al. (2021) The m(6)A reader IMP2 directs autoimmune inflammation through an IL-17- and TNFalpha-dependent C/EBP transcription factor axis. Sci Immunol 6(61):eabd1287 |
| abstractText | Excessive cytokine activity underlies many autoimmune conditions, particularly through the interleukin-17 (IL-17) and tumor necrosis factor-alpha (TNFalpha) signaling axis. Both cytokines activate nuclear factor kappaB, 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(6)A)] in regulating C/EBPbeta and C/EBPdelta in response to IL-17A, as well as IL-17F and TNFalpha. Prompted by the observation that C/EBPbeta/delta-encoding transcripts contain m(6)A consensus sites, we show that Cebpd and Cebpb mRNAs are subject to m(6)A modification. Induction of C/EBPs is enhanced by an m(6)A methylase "writer" and suppressed by a demethylase "eraser." The only m(6)A "reader" found to be involved in this pathway was IGF2BP2 (IMP2), and IMP2 occupancy of Cebpd and Cebpb mRNA was enhanced by m(6)A modification. IMP2 facilitated IL-17-mediated Cebpd mRNA stabilization and promoted translation of C/EBPbeta/delta in response to IL-17A, IL-17F, and TNFalpha. 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 Cebpb and Cebpd Lipocalin-2 (Lcn2), a hallmark of autoimmune kidney injury, was strongly dependent on IL-17, IMP2, and C/EBPbeta/delta. Imp2(-/-) mice were resistant to autoantibody-induced glomerulonephritis (AGN), showing impaired renal expression of C/EBPs and Lcn2 Moreover, IMP2 deletion initiated only after AGN onset ameliorated disease. Thus, posttranscriptional regulation of C/EBPs through m(6)A/IMP2 represents a previously unidentified paradigm of cytokine-driven autoimmune inflammation. |
