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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2023-11, Vol.120 (48), p.e2309205120-e2309205120
• Main Authors: Schmidt, Henrik, Raj, Timsse, O'Neill, Thomas J., Muschaweckh, Andreas, Giesert, Florian, Negraschus, Arlinda, Hoefig, Kai P., Behrens, Gesine, Esser, Lena, Baumann, Christina, Feederle, Regina, Plaza-Sirvent, Carlos, Geerlof, Arie, Gewies, Andreas, Isay, Sophie E., Ruland, Jürgen, Schmitz, Ingo, Wurst, Wolfgang, Korn, Thomas, Krappmann, Daniel, Heissmeyer, Vigo
• Format: Article
• Language: English
• Subjects: Affinity; Antigens; Autoimmunity; Cell activation; Cell differentiation; Cleavage; Derepression; Differentiation; Experimental allergic encephalomyelitis; Helper cells; Homeostasis; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Molecular modelling; Paracaspases; RNA-binding protein; Substrates; T cell receptors; TRAF6 protein
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2309205120

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.