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. 2014 Nov;15(11):1079-89.
doi: 10.1038/ni.3008. Epub 2014 Oct 5.

Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote T(H)17 differentiation

Katharina M Jeltsch  1 , Desheng Hu  2 , Sven Brenner  2 , Jessica Zöller  3 , Gitta A Heinz  2 , Daniel Nagel  4 , Katharina U Vogel  2 , Nina Rehage  1 , Sebastian C Warth  2 , Stephanie L Edelmann  1 , Renee Gloury  5 , Nina Martin  2 , Claudia Lohs  2 , Maciej Lech  6 , Jenny E Stehklein  2 , Arie Geerlof  7 , Elisabeth Kremmer  2 , Achim Weber  8 , Hans-Joachim Anders  6 , Ingo Schmitz  9 , Marc Schmidt-Supprian  10 , Mingui Fu  11 , Helmut Holtmann  12 , Daniel Krappmann  4 , Jürgen Ruland  13 , Axel Kallies  5 , Mathias Heikenwalder  3 , Vigo Heissmeyer  1
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Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote T(H)17 differentiation

Katharina M Jeltsch et al. Nat Immunol. 2014 Nov.

Abstract

Humoral autoimmunity paralleled by the accumulation of follicular helper T cells (T(FH) cells) is linked to mutation of the gene encoding the RNA-binding protein roquin-1. Here we found that T cells lacking roquin caused pathology in the lung and accumulated as cells of the T(H)17 subset of helper T cells in the lungs. Roquin inhibited T(H)17 cell differentiation and acted together with the endoribonuclease regnase-1 to repress target mRNA encoding the T(H)17 cell-promoting factors IL-6, ICOS, c-Rel, IRF4, IκBNS and IκBζ. This cooperation required binding of RNA by roquin and the nuclease activity of regnase-1. Upon recognition of antigen by the T cell antigen receptor (TCR), roquin and regnase-1 proteins were cleaved by the paracaspase MALT1. Thus, this pathway acts as a 'rheostat' by translating TCR signal strength via graded inactivation of post-transcriptional repressors and differential derepression of targets to enhance T(H)17 differentiation.

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