TY - JOUR
T1 - The m6A reader IMP2 directs autoimmune inflammation through an IL-17 and TNFα-dependent C/EBP transcription factor axis
AU - Bechara, Rami
AU - Amatya, Nilesh
AU - Bailey, Rachel D.
AU - Li, Yang
AU - Aggor, Felix E.Y.
AU - Li, De Dong
AU - Jawale, Chetan V.
AU - Coleman, Bianca M.
AU - Dai, Ning
AU - Gokhale, Nandan S.
AU - Taylor, Tiffany C.
AU - Horner, Stacy M.
AU - Poholek, Amanda C.
AU - Bansal, Anita
AU - Biswas, Partha S.
AU - Gaffen, Sarah L.
N1 - Publisher Copyright:
© 2021 American Association for the Advancement of Science. All rights reserved.
PY - 2021/7
Y1 - 2021/7
N2 - 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 B, 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 (m6A)] in regulating C/EBP-and C/EBP-in response to IL-17A, as well as IL-17F and TNFα. Prompted by the observation that C/EBP-/-encoding transcripts contain m6A consensus sites, we show that Cebpd and Cebpb mRNAs are subject to m6A modification. Induction of C/EBPs is enhanced by an m6A methylase "writer" and suppressed by a demethylase "eraser." The only m6A "reader" found to be involved in this pathway was IGF2BP2 (IMP2), and IMP2 occupancy of Cebpd and Cebpb mRNA was enhanced by m6A modification. IMP2 facilitated IL-17 mediated Cebpd mRNA stabilization and promoted translation of C/EBP-/-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 Cebpb and Cebpd. Lipocalin-2 (Lcn2), a hallmark of autoimmune kidney injury, was strongly dependent on IL-17, IMP2, and C/EBP-/-. 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 m6A/IMP2 represents a previously unidentified paradigm of cytokine-driven autoimmune inflammation.
AB - 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 B, 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 (m6A)] in regulating C/EBP-and C/EBP-in response to IL-17A, as well as IL-17F and TNFα. Prompted by the observation that C/EBP-/-encoding transcripts contain m6A consensus sites, we show that Cebpd and Cebpb mRNAs are subject to m6A modification. Induction of C/EBPs is enhanced by an m6A methylase "writer" and suppressed by a demethylase "eraser." The only m6A "reader" found to be involved in this pathway was IGF2BP2 (IMP2), and IMP2 occupancy of Cebpd and Cebpb mRNA was enhanced by m6A modification. IMP2 facilitated IL-17 mediated Cebpd mRNA stabilization and promoted translation of C/EBP-/-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 Cebpb and Cebpd. Lipocalin-2 (Lcn2), a hallmark of autoimmune kidney injury, was strongly dependent on IL-17, IMP2, and C/EBP-/-. 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 m6A/IMP2 represents a previously unidentified paradigm of cytokine-driven autoimmune inflammation.
UR - https://www.scopus.com/pages/publications/85109294400
U2 - 10.1126/sciimmunol.abd1287
DO - 10.1126/sciimmunol.abd1287
M3 - Article
C2 - 34215679
AN - SCOPUS:85109294400
SN - 2470-9468
VL - 6
JO - Science Immunology
JF - Science Immunology
IS - 61
M1 - eabd1287
ER -