TY - JOUR
T1 - A20 negatively regulates T cell receptor signaling to NF-κB by cleaving Malt1 ubiquitin chains
AU - Düwel, Michael
AU - Welteke, Verena
AU - Oeckinghaus, Andrea
AU - Baens, Mathijs
AU - Kloo, Bernhard
AU - Ferch, Uta
AU - Darnay, Bryant G.
AU - Ruland, Jürgen
AU - Marynen, Peter
AU - Krappmann, Daniel
N1 - Copyright:
Copyright 2010 Elsevier B.V., All rights reserved.
PY - 2009/6/15
Y1 - 2009/6/15
N2 - The Carma1-Bcl10-Malt1 signaling module bridges TCR signaling to the canonical IκB kinase (IKK)/NF-κB 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-κB 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-κB 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-κB signaling.
AB - The Carma1-Bcl10-Malt1 signaling module bridges TCR signaling to the canonical IκB kinase (IKK)/NF-κB 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-κB 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-κB 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-κB signaling.
UR - http://www.scopus.com/inward/record.url?scp=67649229160&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=67649229160&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.0803313
DO - 10.4049/jimmunol.0803313
M3 - Article
C2 - 19494296
AN - SCOPUS:67649229160
SN - 0022-1767
VL - 182
SP - 7718
EP - 7728
JO - Journal of Immunology
JF - Journal of Immunology
IS - 12
ER -