Oncogenic CARD11 mutations induce hyperactive signaling by disrupting autoinhibition by the PKC-responsive inhibitory domain.
The regulated activation of NF-κB by antigen receptor signaling is required for normal B and T lymphocyte activation during the adaptive immune response. Dysregulated NF-κB activation is associated with several types of lymphoma, including diffuse large B cell lymphoma (DLBCL). During normal antigen receptor signaling, the multidomain scaffold protein CARD11 undergoes a transition from a closed, inactive state to an open, active conformation that recruits several signaling proteins into a complex, leading to IKK kinase activation. This transition is regulated by the CARD11 inhibitory domain (ID), which participates in intramolecular interactions that prevent cofactor binding to CARD11 prior to signaling, but which is neutralized after receptor engagement by phosphorylation. Several oncogenic CARD11 mutations have been identified in DLBCL that enhance activity and that are mostly found in the coiled-coil domain. However, the mechanisms by which these mutations cause CARD11 hyperactivity and spontaneous NF-κB activation are poorly understood. In this report, we provide several lines of evidence that oncogenic mutations F123I and L225LI induce CARD11 hyperactivity by disrupting autoinhibition by the CARD11 ID. These mutations disrupt ID-mediated intramolecular interactions and ID-dependent inhibition and bypass the requirement for ID phosphorylation during T cell receptor signaling. Intriguingly, these mutations selectively enhance the apparent affinity of CARD11 for Bcl10, but not for other signaling proteins that are recruited to CARD11 in an ID-dependent manner during normal antigen receptor signaling. Our results establish a mechanism that explains how DLBCL-associated mutations in CARD11 can initiate spontaneous, receptor-independent activation of NF-κB.
Lamason
Rebecca L
RL
Department of Biological Chemistry and Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
McCully
Ryan R
RR
Lew
Stefanie M
SM
Pomerantz
Joel L
JL
D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics*; D002273:Carcinogens; D006162:Guanylate Cyclase / Q000235:genetics*; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011946:Receptors, Antigen / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; D053468:CARD Signaling Adaptor Proteins; D002273:Carcinogens; D016328:NF-kappa B; D011946:Receptors, Antigen; D011493:Protein Kinase C; C426242:CARD11 protein, human; D006162:Guanylate Cyclase
Immunity. 2005 Dec;23(6):575-85
16356856
Immunity. 2006 Nov;25(5):701-15
17098202
Trends Immunol. 2007 Jun;28(6):281-8
17468049
Nat Rev Immunol. 2006 Nov;6(11):799-812
17063183
Immunity. 2003 Nov;19(5):749-58
14614861
Immunity. 2005 Dec;23(6):561-74
16356855
Leuk Lymphoma. 2003;44 Suppl 3:S41-7
15202524
Nature. 2009 Jun 4;459(7247):717-21
19412164
EMBO J. 2007 Nov 14;26(22):4634-45
17948050
Nature. 2006 May 4;441(7089):106-10
16572121
Science. 2005 Mar 4;307(5714):1465-8
15746428
Science. 2008 Mar 21;319(5870):1676-9
18323416
Cold Spring Harb Perspect Biol. 2010 May;2(5):a000182
20452952
EMBO J. 2002 Oct 1;21(19):5184-94
12356734
Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3023-8
18287044
EMBO J. 2007 Apr 4;26(7):1794-805
17363905
Mol Cell. 2004 May 7;14(3):289-301
15125833
Mol Cell Biol. 2008 Sep;28(18):5668-86
18625728
Nature. 2004 Jan 8;427(6970):167-71
14695475
J Biol Chem. 2001 Jun 1;276(22):19012-9
11262391
Immunol Rev. 2009 Mar;228(1):199-211
19290929
J Biol Chem. 2004 Apr 16;279(16):15870-6
14754896