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Schmidt, H.* ; Raj, T.* ; O´Neill, T.J. ; Muschaweckh, A.* ; Giesert, F. ; Negraschus, A.* ; Hoefig, K.P. ; Behrens, G.* ; Esser, L.* ; Baumann, Christina ; Feederle, R. ; Plaza-Sirvent, C.* ; Geerlof, A. ; Gewies, A. ; Isay, S.E.* ; Ruland, J.* ; Schmitz, I.* ; Wurst, W. ; Korn, T.* ; Krappmann, D. ; Heissmeyer, V.

Unrestrained cleavage of Roquin-1 by MALT1 induces spontaneous T cell activation and the development of autoimmunity.

Proc. Natl. Acad. Sci. U.S.A. 120, 11:e2309205120 (2023)
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Constitutive activation of the MALT1 paracaspase in conventional T cells of Malt1TBM/TBM (TRAF6 Binding Mutant = TBM) mice causes fatal inflammation and autoimmunity, but the involved targets and underlying molecular mechanisms are unknown. We genetically rendered a single MALT1 substrate, the RNA-binding protein (RBP) Roquin-1, insensitive to MALT1 cleavage. These Rc3h1Mins/Mins mice showed normal immune homeostasis. Combining Rc3h1Mins/Mins alleles with those encoding for constitutively active MALT1 (TBM) prevented spontaneous T cell activation and restored viability of Malt1TBM/TBM mice. Mechanistically, we show how antigen/MHC recognition is translated by MALT1 into Roquin cleavage and derepression of Roquin targets. Increasing T cell receptor (TCR) signals inactivated Roquin more effectively, and only high TCR strength enabled derepression of high-affinity targets to promote Th17 differentiation. Induction of experimental autoimmune encephalomyelitis (EAE) revealed increased cleavage of Roquin-1 in disease-associated Th17 compared to Th1 cells in the CNS. T cells from Rc3h1Mins/Mins mice did not efficiently induce the high-affinity Roquin-1 target IκBNS in response to TCR stimulation, showed reduced Th17 differentiation, and Rc3h1Mins/Mins mice were protected from EAE. These data demonstrate how TCR signaling and MALT1 activation utilize graded cleavage of Roquin to differentially regulate target mRNAs that control T cell activation and differentiation as well as the development of autoimmunity.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Antigen Receptor Signaling ; Autoimmunity ; Paracaspase ; Rna-binding Protein ; T Cell Differentiation; Constitutive-decay Element; Messenger-rna Decay; Fate Decisions; T-h-17 Cells; Effector T; Receptor; Regnase-1; Recognition; Deficiency; Expression
ISSN (print) / ISBN 0027-8424
e-ISSN 1091-6490
Quellenangaben Volume: 120, Issue: 48, Pages: 11, Article Number: e2309205120 Supplement: ,
Publisher National Academy of Sciences
Publishing Place 2101 Constitution Ave Nw, Washington, Dc 20418 Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Abteilung für Molekulare Immunregulation (AMIR)
Research Unit Signaling and Translation (SAT)
Institute of Developmental Genetics (IDG)
CF Monoclonal Antibodies (CF-MAB)
Institute of Structural Biology (STB)
Grants Deutsche Forschungsgemeinschaft (DFG)