RNA m6A methylation guides IL-17-driven autoimmunity through IMP2-dependent regulation of C/EBP transcription factors

• Published in: The Journal of immunology (1950) Vol. 206; no. 1_Supplement; pp. 22 - 22.06
• Main Authors: Bechara, Rami, Amatya, Nilesh, Bailey, Rachel D., Li, Yang, Aggor, Felix EY, Li, De-Dong, Jawale, Chetan V., Coleman, Bianca M., Dai, Ning, Gokhale, Nandan S., Taylor, Tiffany C., Horner, Stacy M., Poholek, Amanda C., Biswas, Partha S., Gaffen, Sarah L.
• Format: Journal Article
• Language: English
• Published: 01.05.2021
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.206.Supp.22.06

Abstract Dysregulated activity of IL-17 underlies many autoimmune conditions, but the molecular mechanisms by which IL-17 mediates pathogenic inflammation remain poorly understood. IL-17 regulates pathogenic inflammatory genes by two key transcription factor classes, NF-κB and CCAAT/Enhancer Binding (C/EBP) proteins. Surprisingly little is known about mechanisms that activate C/EBPs. In seeking to understand how IL-17 upregulates C/EBPs, we found that IL-17 signaling enhanced Cebpd mRNA stability, concomitant with increased levels of C/EBPδ translation. In contrast, IL-17 had only a marginal inductive effect on Cebpb mRNA, yet C/EBPβ protein was strongly upregulated. Examination of Cebpb and Cebpd noncoding sequences identified consensus sites for N6-methyladenosine (m6A) modification, an epitranscriptomic mark that influences mRNA fate. knockdown of the m6A ‘writer’ METTL3 decreased C/EBP expression, which was reversed by the ‘eraser’ FTO. Moreover, we found that loss of an unusual m6A ‘reader’ IGF2BP2 (IMP2), an RNA binding protein known to control mRNA stability, impaired IL-17 induction of C/EBPs. IMP2 bound directly to Cebps transcripts, leading to enhanced Cebpd half-life and enhanced translation of both C/EBPs. Transcriptomic analysis revealed that IMP2 regulates C/EBP-dependent genes, including IL-6 and Lcn2. Lcn2 is a biomarker of autoantibody-induced glomerulonephritis (AGN), a setting of IL-17-driven inflammatory nephritis. Imp2−/− mice were resistant to AGN, which was linked to impaired upregulation of C/EPBs and Lcn2 in kidney. Thus, IL-17-induced autoimmunity is mediated through m6A-dependent post-transcriptional regulation of C/EBP transcription factors.