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A20 Negatively Regulates T Cell Receptor Signaling to NF-B by Cleaving Malt1 Ubiquitin Chains¹

Michael Düwel^*, Verena Welteke^2,*, Andrea Oeckinghaus^2,*, Mathijs Baens^,, Bernhard Kloo^*, Uta Ferch, Bryant G. Darnay^¶, Jürgen Ruland, Peter Marynen^, and Daniel Krappmann^3,*

^* Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Toxicology, Neuherberg, Germany; Human Genome Laboratory, Molecular Genetics, Center for Human Genetics, University of Leuven, Leuven, Belgium; Human Genome Laboratory, Department of Molecular and Developmental Genetics, Flanders Institute for Biotechnology, Leuven, Belgium; III. Medical Department, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; and ^¶ Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX

The Carma1-Bcl10-Malt1 signaling module bridges TCR signaling to the canonical IB kinase (IKK)/NF-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-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-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-B signaling.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by DFG grants to D.K. (DK2306/1; DK2306/2).

² V.W. and A.O. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Daniel Krappmann, Institute of Toxicology, Helmholtz Zentrum Muenchen, P.O. Box 11 29, 85758 Neuherberg. E-mail address: Daniel.Krappmann{at}helmholtz-muenchen.de

⁴ Abbreviations used in this paper: IKK, IB kinase; CARD, caspase recruitment domain; CBM, Carma1-Malt1-Bcl10; CYLD, cylindromatosis; DUB, deubiquitinating enzyme; EMSA, electrophoretic mobility shift assay; IRES, internal ribosome entry site; NEM, N-ethylmaleimide; P/I, PMA/ionomycin; PKC, protein kinase C; siRNA, small interfering RNA; wt, wild type; IP, immunoprecipitation.