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Title: A20 Negatively Regulates T Cell Receptor Signaling to NF-kappa B by Cleaving Malt1 Ubiquitin Chains
Authors: Duewel, Michael
Welteke, Verena
Oeckinghaus, Andrea
Baens, Thijs
Kloo, Bernhard
Ferch, Uta
Darnay, Bryant G
Ruland, Juergen
Marynen, Peter
Krappmann, Daniel # ×
Issue Date: Jun-2009
Publisher: American Association of Immunologists
Series Title: Journal of Immunology vol:182 issue:12 pages:7718-7728
Abstract: 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. The Journal of Immunology, 2009, 182: 7718-7728.
ISSN: 0022-1767
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Human Genome Laboratory
Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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