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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)
DOI PMC
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter 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
Zeitschrift Proceedings of the National Academy of Sciences of the United States of America
Quellenangaben Band: 120, Heft: 48, Seiten: 11, Artikelnummer: e2309205120 Supplement: ,
Verlag National Academy of Sciences
Verlagsort 2101 Constitution Ave Nw, Washington, Dc 20418 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) 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)
Förderungen Deutsche Forschungsgemeinschaft (DFG)