CARMA1 is a critical lipid raft–associated regulator of TCR-induced NF-κB activation

Abstract

CARMA1 is a lymphocyte-specific member of the membrane-associated guanylate kinase (MAGUK) family of scaffolding proteins, which coordinate signaling pathways emanating from the plasma membrane. CARMA1 interacts with Bcl10 via its caspase-recruitment domain (CARD). Here we investigated the role of CARMA1 in T cell activation and found that T cell receptor (TCR) stimulation induced a physical association of CARMA1 with the TCR and Bcl10. We found that CARMA1 was constitutively associated with lipid rafts, whereas cytoplasmic Bcl10 translocated into lipid rafts upon TCR engagement. A CARMA1 mutant, defective for Bcl10 binding, had a dominant-negative (DN) effect on TCR-induced NF-kappa B activation and IL-2 production and on the c-Jun NH(2)-terminal kinase (Jnk) pathway when the TCR was coengaged with CD28. Together, our data show that CARMA1 is a critical lipid raft-associated regulator of TCR-induced NF-kappa B activation and CD28 costimulation-dependent Jnk activation.

Potential role of CARMA1 in CD40‐induced splenic B cell proliferation and marginal zone B cell maturation

“…CARMA1 has been recently identified as an essential component for the activation of transcription factor NF-jB upon antigen receptor activation in T and B cells [20][21][22]24]. In B cells, CARMA1 deficiency results in defective proliferation upon BCR stimulation and CARMA1 KO mice are defective in mounting humoral immune responses [20,23,24].…”

“…Recent studies have identified a novel scaffold protein CARMA1 (CARD domain and membrane associated-guanylate kinase domain-containing protein-1) as an essential component involved in NF-jB activation upon antigenic stimulation in both T and B lymphocytes [19][20][21][22]. CARMA1-deficient B cells are defective in activation and proliferation upon BCR stimulation and in humoral immune responses [23,24].…”

NF-κB and the immune response

“…What is surprising however, as mentioned above, is the lack of a role for this complex in developing lymphocytes, and by extrapolation signaling through the pre-AgRs. The MAGUK family protein CARMA1 is required for activation of NF-kB in T cells following TCR ligation, but its loss has no effect on the development of thymocyte (Gaide et al, 2002;Egawa et al, 2003;Hara et al, 2003). Similarly, BCL10 is critical for NF-kB activation via the BCR and TCR, yet normal numbers of peripheral T cells are seen in BCL10 knockouts, and no clear defects in B-cell development is observed (Ruland et al, 2001).…”

Novel CARD11 Mutations in Human Cutaneous Squamous Cell Carcinoma Lead to Aberrant NF-κB Regulation

“…It is important to note that CARD scaffold proteins can signal through pathways other than NF-kB, such as Jun N-terminal kinase. 42,43 The identification of cSCC mutations in the CARD and GUK domains that abolish CARD11-mediated NF-kB activation yet maintain signalosome formation may be indicative of differential signaling. Similar variants in CARD14, which reduced NF-kB activation in 293 cells in vitro, also were identified in psoriasis patients, 24 therefore further work will be needed to determine whether CARD11 and CARD14 do indeed mediate differential signaling in keratinocytes.…”

“…Another possibility is that cSCC variants that abolish NF-kB activation reflect the published contextdependent role of NF-kB signaling in keratinocytes 10,11,44 and, given the correct context, reduction of NF-kB signaling through CARD11 mutation may be tumor promoting. Those CARD11 variants that abolish NF-kB activation may result from disruption of essential proteineprotein interactions such as association with BCL10 40,43 and PDK1, 39 both of which are crucial for pathway activation.…”