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

Schmidt H, Raj T, O'Neill TJ, Muschaweckh A, Giesert F, Negraschus A, Hoefig KP, Behrens G, Esser L, Baumann C, Feederle R, Plaza-Sirvent C, Geerlof A, Gewies A, Isay SE, Ruland J, Schmitz I, Wurst W, Korn T, Krappmann D, Heissmeyer V (2023 Nov 28) 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(48):e2309205120. doi: 10.1073/pnas.2309205120. (Projects A03, A04, B01, B06)

Abstract cited directly from the article:

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 IκBNS 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 the development of autoimmunity.