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

作者：Henrik Schmidt, Timsse Raj, Thomas J. O’Neill, Andreas Muschaweckh, Florian Giesert, Arlinda Negraschus, Kai P. Hoefig, Gesine Behrens, Lena Esser, Christina Baumann, Regina Feederle, Carlos Plaza‐Sirvent, Arie Geerlof, Andreas Gewies, Sophie E. Isay, Jürgen Ruland, Ingo Schmitz, Wolfgang Wurst, Thomas Korn, Daniel Krappmann, Vigo Heissmeyer · 发表于：Proceedings of the National Academy of Sciences · 年份：2023 · DOI：10.1073/pnas.2309205120 · 被引用次数：12 · 研究领域：NF-κB Signaling Pathways、Cytokine Signaling Pathways and Interactions、interferon and immune responses

Constitutive activation of the MALT1 paracaspase in conventional T cells of Malt1 TBM/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 Rc3h1 Mins/Mins mice showed normal immune homeostasis. Combining Rc3h1 Mins/Mins alleles with those encoding for constitutively active MALT1 (TBM) prevented spontaneous T cell activation and restored viability of Malt1 TBM/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 Rc3h1 Mins/Mins mice did not efficiently induce the high-affinity Roquin-1 target IκB NS in response to TCR stimulation, showed reduced Th17 differentiation, and Rc3h1 Mins/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 ...