Article | Published:

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

Nature Immunologyvolume 3pages836843 (2002) | Download Citation



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-κB activation and IL-2 production and on the c-Jun NH2-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-κB activation and CD28 costimulation–dependent Jnk activation.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1

    Kane, L.P., Lin, J. & Weiss, A. Signal transduction by the TCR for antigen. Curr. Opin. Immunol. 12, 242–249 (2000).

  2. 2

    Gerondakis, S., Grumont, R., Rourke, I. & Grossmann, M. The regulation and roles of Rel/NF-κB transcription factors during lymphocyte activation. Curr. Opin. Immunol. 10, 353–359 (1998).

  3. 3

    Cantrell, D. T cell antigen receptor signal transduction pathways. Annu. Rev. Immunol. 14, 259–274 (1996).

  4. 4

    Janes, P.W., Ley, S.C., Magee, A.I. & Kabouridis, P.S. The role of lipid rafts in T cell antigen receptor (TCR) signalling. Semin. Immunol. 12, 23–34 (2000).

  5. 5

    Zhang, W., Trible, R.P. & Samelson, L.E. LAT palmitoylation: its essential role in membrane microdomain targeting and tyrosine phosphorylation during T cell activation. Immunity 9, 239–246 (1998).

  6. 6

    Resh, M.D. Fatty acylation of proteins: new insights into membrane targeting of myristoylated and palmitoylated proteins. Biochim. Biophys. Acta 1451, 1–16 (1999).

  7. 7

    Montixi, C. et al. Engagement of T cell receptor triggers its recruitment to low-density detergent-insoluble membrane domains. EMBO J. 17, 5334–5348 (1998).

  8. 8

    Xavier, R., Brennan, T., Li, Q., McCormack, C. & Seed, B. Membrane compartmentation is required for efficient T cell activation. Immunity 8, 723–732 (1998).

  9. 9

    Khoshnan, A., Bae, D., Tindell, C.A. & Nel, A.E. The physical association of protein kinase Cθ with a lipid raft- associated inhibitor of κB factor kinase (IKK) complex plays a role in the activation of the NF-κB cascade by TCR and CD28. J. Immunol. 165, 6933–6940 (2000).

  10. 10

    Bi, K. et al. Antigen-induced translocation of PKC-θ to membrane rafts is required for T cell activation. Nature Immunol. 2, 556–563 (2001).

  11. 11

    Bi, K. & Altman, A. Membrane lipid microdomains and the role of PKCθ in T cell activation. Semin. Immunol. 13, 139–146 (2001).

  12. 12

    Sun, Z. et al. PKC-θ is required for TCR-induced NF-κB activation in mature but not immature T lymphocytes. Nature 404, 402–407 (2000).

  13. 13

    Ruland, J. et al. Bcl10 is a positive regulator of antigen receptor-induced activation of NF-κB and neural tube closure. Cell 104, 33–42 (2001).

  14. 14

    Willis, T.G. et al. Bcl10 is involved in t(1;14)(p22;q32) of MALT B cell lymphoma and mutated in multiple tumor types. Cell 96, 35–45 (1999).

  15. 15

    Zhang, Q. et al. Inactivating mutations and overexpression of BCL10, a caspase recruitment domain-containing gene, in MALT lymphoma with t(1;14)(p22;q32). Nature Genet. 22, 63–68 (1999).

  16. 16

    Gaide, O. et al. CARMA1, a CARD-containing binding partner of Bcl10, induces Bcl10 phosphorylation and NF-κB activation. FEBS Lett. 496, 121–127 (2001).

  17. 17

    McAllister-Lucas, L.M. et al. Bimp1, a MAGUK family member linking protein kinase C activation to Bcl10-mediated NF-κB induction. J. Biol. Chem. 276, 30589–30597 (2001).

  18. 18

    Bertin, J. et al. CARD11 and CARD14 are novel caspase recruitment domain (CARD)/membrane- associated guanylate kinase (MAGUK) family members that interact with BCL10 and activate NF-κB. J. Biol. Chem. 276, 11877–11882 (2001).

  19. 19

    Wang, L. et al. Card10 is a novel caspase recruitment domain/membrane-associated guanylate kinase family member that interacts with BCL10 and activates NF-κB. J. Biol. Chem. 276, 21405–21409 (2001).

  20. 20

    Fanning, A.S. & Anderson, J.M. Protein modules as organizers of membrane structure. Curr. Opin. Cell Biol. 11, 432–439 (1999).

  21. 21

    Dimitratos, S.D., Woods, D.F., Stathakis, D.G. & Bryant, P.J. Signaling pathways are focused at specialized regions of the plasma membrane by scaffolding proteins of the MAGUK family. Bioessays 21, 912–921 (1999).

  22. 22

    Ponting, C.P., Phillips, C., Davies, K.E. & Blake, D.J. PDZ domains: targeting signalling molecules to sub-membranous sites. Bioessays 19, 469–479 (1997).

  23. 23

    Mayer, B.J. SH3 domains: complexity in moderation. J. Cell. Sci. 114, 1253–1263 (2001).

  24. 24

    Thome, M. et al. Equine herpesvirus protein E10 induces membrane recruitment and phosphorylation of its cellular homologue, Bcl10. J. Cell. Biol. 152, 1115–1122 (2001).

  25. 25

    Hsi, E.D. et al. T cell activation induces rapid tyrosine phosphorylation of a limited number of cellular substrates. J. Biol. Chem. 264, 10836–10842 (1989).

  26. 26

    Chan, A.C., Iwashima, M., Turck, C.W. & Weiss, A. ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR ζ chain. Cell 71, 649–662 (1992).

  27. 27

    Janes, P.W., Ley, S.C. & Magee, A.I. Aggregation of lipid rafts accompanies signaling via the T cell antigen receptor. J. Cell Biol. 147, 447–461 (1999).

  28. 28

    Leupin, O., Zaru, R., Laroche, T., Muller, S. & Valitutti, S. Exclusion of CD45 from the T-cell receptor signaling area in antigen-stimulated T lymphocytes. Curr. Biol. 10, 277–280 (2000).

  29. 29

    Legler, D.F., Doucey, M.A., Cerottini, J.C., Bron, C. & Luescher, I.F. Selective inhibition of CTL activation by a dipalmitoyl-phospholipid that prevents the recruitment of signaling molecules to lipid rafts. FASEB J. 15, 1601–1603 (2001).

  30. 30

    Harder, T. & Simons, K. Clusters of glycolipid and glycosylphosphatidylinositol-anchored proteins in lymphoid cells: accumulation of actin regulated by local tyrosine phosphorylation. Eur. J. Immunol. 29, 556–562 (1999).

  31. 31

    Doucey, M.A. et al. CTL activation is induced by cross-linking of TCR/MHC-peptide- CD8/p56lck adducts in rafts. Eur. J. Immunol. 31, 1561–1570 (2001).

  32. 32

    Ilangumaran, S., He, H.T. & Hoessli, D.C. Microdomains in lymphocyte signalling: beyond GPI-anchored proteins. Immunol. Today 21, 2–7 (2000).

  33. 33

    Bordier, C. Phase separation of integral membrane proteins in Triton X-114 solution. J. Biol. Chem. 256, 1604–1607 (1981).

  34. 34

    Schneider, P. et al. Characterization of two receptors for TRAIL. FEBS Lett. 416, 329–334 (1997).

  35. 35

    Kabouridis, P.S., Magee, A.I. & Ley, S.C. S-acylation of LCK protein tyrosine kinase is essential for its signalling function in T lymphocytes. EMBO J. 16, 4983–4998 (1997).

  36. 36

    Jain, J., Loh, C. & Rao, A. Transcriptional regulation of the IL-2 gene. Curr. Opin. Immunol. 7, 333–342 (1995).

  37. 37

    Su, B. et al. JNK is involved in signal integration during costimulation of T lymphocytes. Cell 77, 727–736 (1994).

  38. 38

    Bradley, J.R. & Pober, J.S. Tumor necrosis factor receptor-associated factors (TRAFs). Oncogene 20, 6482–6491 (2001).

  39. 39

    Devin, A. et al. The distinct roles of TRAF2 and RIP in IKK activation by TNF-R1: TRAF2 recruits IKK to TNF-R1 while RIP mediates IKK activation. Immunity 12, 419–429 (2000).

  40. 40

    Wang, C. et al. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 412, 346–351 (2001).

  41. 41

    Thome, M. et al. Equine herpesvirus-2 E10 gene product, but not its cellular homologue, activates NF-κB transcription factor and c-Jun N-terminal kinase. J. Biol. Chem. 274, 9962–9968 (1999).

  42. 42

    Yoneda, T. et al. Regulatory mechanisms of TRAF2-mediated signal transduction by Bcl10, a MALT lymphoma-associated protein. J. Biol. Chem. 275, 11114–11120 (2000).

  43. 43

    Uren, A.G. et al. Identification of paracaspases and metacaspases: two ancient families of caspase-like proteins, one of which plays a key role in MALT lymphoma. Mol. Cell 6, 961–967 (2000).

  44. 44

    Dierlamm, J. et al. The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21)p6ssociated with mucosa- associated lymphoid tissue lymphomas. Blood 93, 3601–3609 (1999).

  45. 45

    Akagi, T. et al. A novel gene, MALT1 at 18q21, is involved in t(11;18) (q21;q21) found in low-grade B-cell lymphoma of mucosa-associated lymphoid tissue. Oncogene 18, 5785–5794 (1999).

  46. 46

    Morgan, J.A. et al. Breakpoints of the t(11;18)(q21;q21) in mucosa-associated lymphoid tissue (MALT) lymphoma lie within or near the previously undescribed gene MALT1 in chromosome 18. Cancer Res. 59, 6205–6213 (1999).

  47. 47

    Lucas, P.C. et al. Bcl10 and MALT1, independent targets of chromosomal translocation in malt lymphoma, cooperate in a novel NF-κ B signaling pathway. J. Biol. Chem. 276, 19012–19019 (2001).

  48. 48

    Ghaffari-Tabrizi, N. et al. Protein kinase Cθ, a selective upstream regulator of JNK/SAPK and IL-2 promoter activation in Jurkat T cells. Eur. J. Immunol. 29, 132–142 (1999).

  49. 49

    Alegre, M.L., Frauwirth, K.A. & Thompson, C.B. T-cell regulation by CD28 and CTLA-4. Nature Rev. Immunol. 1, 220–228 (2001).

  50. 50

    Penna, D. et al. Degradation of ZAP-70 after antigenic stimulation in human T lymphocytes: role of calpain proteolytic pathway. J. Immunol. 163, 50–56 (1999).

Download references


Supported by grants from the Swiss Cancer League (to M. T. and J. T.) and by the Swiss Academy of Medical Sciences (to O. G). C. B. and D. L. were supported by grants from the Swiss National Science Foundation and the Giorgi Cavaglieri Foundation; S. V. was supported by grants from La Ligue contre le Cancer, La Fondation pour la Recherche Médicale and the Giorgio Cavaglieri Foundation. We thank S. Levrand for technical assistance, P. Zaech for help with FACS analysis and K. Burns, F. Martinon and M. Thurau for critical review of the manuscript.

Author information

Author notes

  1. Olivier Gaide and Benoît Favier: These authors contributed equally to this work.


  1. Institute of Biochemistry, University of Lausanne, BIL Biomedical Research Center, Chemin des Boveresses 155, Epalinges, CH-1066, Switzerland

    • Olivier Gaide
    • , Daniel F. Legler
    • , David Bonnet
    • , Brian Brissoni
    • , Claude Bron
    • , Jürg Tschopp
    •  & Margot Thome
  2. INSERM U563, Institut Claude de Préval, CHU Purpan, Toulouse, F-31059, France

    • Benoît Favier
    •  & Salvatore Valitutti


  1. Search for Olivier Gaide in:

  2. Search for Benoît Favier in:

  3. Search for Daniel F. Legler in:

  4. Search for David Bonnet in:

  5. Search for Brian Brissoni in:

  6. Search for Salvatore Valitutti in:

  7. Search for Claude Bron in:

  8. Search for Jürg Tschopp in:

  9. Search for Margot Thome in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Margot Thome.

About this article

Publication history




Issue Date


Further reading