A20 Negatively Regulates T Cell Receptor Signaling to NF-κB by Cleaving Malt1 Ubiquitin Chains

DOI PDF 5 Citations
  • Michael Düwel
    Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Toxicology , Neuherberg,
  • Verena Welteke
    Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Toxicology , Neuherberg,
  • Andrea Oeckinghaus
    Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Toxicology , Neuherberg,
  • Mathijs Baens
    Human Genome Laboratory, Molecular Genetics, Center for Human Genetics, University of Leuven , Leuven,
  • Bernhard Kloo
    Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Toxicology , Neuherberg,
  • Uta Ferch
    Medical Department, Klinikum rechts der Isar, Technical University of Munich , Munich,
  • Bryant G Darnay
    Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center , Houston, TX
  • Jürgen Ruland
    Medical Department, Klinikum rechts der Isar, Technical University of Munich , Munich,
  • Peter Marynen
    Human Genome Laboratory, Molecular Genetics, Center for Human Genetics, University of Leuven , Leuven,
  • Daniel Krappmann
    Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Toxicology , Neuherberg,

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<jats:title>Abstract</jats:title> <jats:p>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.</jats:p>

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