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Düwel, M. ; Welteke, V. ; Oeckinghaus, A. ; Baens, M.* ; Kloo, B. ; Ferch, U.* ; Darnay, B.G.* ; Ruland, J.* ; Marynen, P.* ; Krappmann, D.

A20 negatively regulates T cell receptor signaling to NF-κB by cleaving Malt1 ubiquitin chains.

J. Immunol. 182, 7718-7728 (2009)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
The Carmal-Bcl10-Malt1 signaling module bridges TCR signaling to the canonical I kappa B kinase (IKK)/NF-kappa B pathway. Covalent attachment of regulatory ubiquitin chains to Malt1 paracaspase directs TCR signaling to IKK activation. Further, the ubiquitin-editing enzyme A20 was recently suggested to suppress T cell activation, but molecular targets for A20 remain elusive. In this paper, we show that A20 regulates the strength and duration of the IKK/NF-kappa B response upon TCR/CD28 costimulation. By catalyzing the removal of K63-linked ubiquitin chains from Malt1, A20 prevents sustained interaction between ubiquitinated Malt1 and the IKK complex and thus serves as a negative regulator of inducible IKK activity. Upon T cell stimulation, A20 is rapidly removed and paracaspase activity of Malt1 has been suggested to cleave A20. Using antagonistic peptides or reconstitution of Malt1(-/-) T cells, we show that Malt1 paracaspase activity is required for A20 cleavage and optimal IL-2 production, but dispensable for initial IKK/NF-kappa B signaling in CD4(+) T cells. However, proteasomal inhibition impairs A20 degradation and impedes TCR/CD28-induced IKK activation. Taken together, A20 functions as a Malt1 deubiquitinating enzyme and proteasomal degradation and de novo synthesis of A20 contributes to balance TCR/CD28-induced IKK/NF-kappa B signaling.
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Publication type Article: Journal article
Document type Scientific Article
Keywords antigen-receptor; lymphocyte-proliferation; paracaspase malt1; inhibitor a20; activation; bcl10; requirement; caspase-8; ligase; enzyme
ISSN (print) / ISBN 0022-1767
e-ISSN 1550-6606
Journal Journal of Immunology
Quellenangaben Volume: 182, Issue: 12, Pages: 7718-7728 Article Number: , Supplement: ,
Publisher American Association of Immunologists
Reviewing status Peer reviewed
Institute(s) Research Unit Signaling and Translation (SAT)