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

ABSTRACT: 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 target

SUBMITTER: Schmidt H 

PROVIDER: S-EPMC10691344 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature