Phosphorylation of serine-893 in CARD11 suppresses the formation and activity of the CARD11-BCL10-MALT1 complex in T and B cells
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Phosphorylation of serine-893 in CARD11 suppresses the formation and activity of the CARD11-BCL10-MALT1 complex in T and B cells. / Kutzner, Kerstin; Woods, Simone; Karayel, Ozge; Gehring, Torben; Yin, Hongli; Flatley, Andrew; Graß, Carina; Wimberger, Nicole; Tofaute, Marie J; Seeholzer, Thomas; Feederle, Regina; Mann, Matthias; Krappmann, Daniel.
I: Science Signaling, Bind 15, Nr. 723, 03.2022, s. eabk3083.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Phosphorylation of serine-893 in CARD11 suppresses the formation and activity of the CARD11-BCL10-MALT1 complex in T and B cells
AU - Kutzner, Kerstin
AU - Woods, Simone
AU - Karayel, Ozge
AU - Gehring, Torben
AU - Yin, Hongli
AU - Flatley, Andrew
AU - Graß, Carina
AU - Wimberger, Nicole
AU - Tofaute, Marie J
AU - Seeholzer, Thomas
AU - Feederle, Regina
AU - Mann, Matthias
AU - Krappmann, Daniel
PY - 2022/3
Y1 - 2022/3
N2 - 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 Ser893 in the carboxyl terminus of CARD11 prevented the activation of the transcription factor NF-κB, the kinase JNK, and the protease MALT1. Moreover, CARD11 Ser893 phosphorylation sensitized BCR-addicted lymphoma cells to toxicity induced by Bruton's tyrosine kinase (BTK) inhibitors. Phosphorylation of Ser893 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.
AB - 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 Ser893 in the carboxyl terminus of CARD11 prevented the activation of the transcription factor NF-κB, the kinase JNK, and the protease MALT1. Moreover, CARD11 Ser893 phosphorylation sensitized BCR-addicted lymphoma cells to toxicity induced by Bruton's tyrosine kinase (BTK) inhibitors. Phosphorylation of Ser893 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.
KW - B-Cell CLL-Lymphoma 10 Protein/genetics
KW - B-Lymphocytes/metabolism
KW - CARD Signaling Adaptor Proteins/genetics
KW - Guanylate Cyclase/genetics
KW - Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein/genetics
KW - NF-kappa B/genetics
KW - Phosphorylation
KW - Serine
U2 - 10.1126/scisignal.abk3083
DO - 10.1126/scisignal.abk3083
M3 - Journal article
C2 - 35230873
VL - 15
SP - eabk3083
JO - Science Signaling
JF - Science Signaling
SN - 1945-0877
IS - 723
ER -
ID: 303113677