Phosphorylation of serine-893 in CARD11 suppresses the formation and activity of the CARD11-BCL10-MALT1 complex in T and B cells

Author:

Kutzner Kerstin1ORCID,Woods Simone1ORCID,Karayel Ozge2ORCID,Gehring Torben1,Yin Hongli1,Flatley Andrew3ORCID,Graß Carina1,Wimberger Nicole1ORCID,Tofaute Marie J.1,Seeholzer Thomas1ORCID,Feederle Regina3ORCID,Mann Matthias2ORCID,Krappmann Daniel1ORCID

Affiliation:

1. Research Unit Cellular Signal Integration, Helmholtz Zentrum München–German Research Center for Environmental Health. Ingolstaedter Landstr. 1, 85764 Neuherberg, Germany.

2. Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Planegg, Germany.

3. Monoclonal Antibody Core Facility, Institute for Diabetes and Obesity, Helmholtz Zentrum München–German Research Center for Environmental Health, Ingolstaedter Landstr. 1, 85764 Neuherberg, Germany.

Abstract

CARD11 acts as a gatekeeper for adaptive immune responses after T cell or B cell antigen receptor (TCR/BCR) ligation on lymphocytes. PKCθ/β-catalyzed phosphorylation of CARD11 promotes the assembly of the CARD11-BCL10-MALT1 (CBM) complex and lymphocyte activation. Here, we demonstrated that PKCθ/β-dependent CARD11 phosphorylation also suppressed CARD11 functions in T or B cells. Through mass spectrometry–based proteomics analysis, we identified multiple constitutive and inducible CARD11 phosphorylation sites in T cells. We demonstrated that a single TCR- or BCR-inducible phosphorylation on Ser 893 in the carboxyl terminus of CARD11 prevented the activation of the transcription factor NF-κB, the kinase JNK, and the protease MALT1. Moreover, CARD11 Ser 893 phosphorylation sensitized BCR-addicted lymphoma cells to toxicity induced by Bruton’s tyrosine kinase (BTK) inhibitors. Phosphorylation of Ser 893 in CARD11 by PKCθ controlled the strength of CARD11 scaffolding by impairing the formation of the CBM complex. Thus, PKCθ simultaneously catalyzes both stimulatory and inhibitory CARD11 phosphorylation events, which shape the strength of CARD11 signaling in lymphocytes.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Cell Biology,Molecular Biology,Biochemistry

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