The CARD11-BCL10-MALT1 (CBM) signalosome complex: Stepping into the limelight of human primary immunodeficiency

Turvey, Stuart E.; Durandy, Anne; Fischer, Alain; Fung, Shan‐Yu; Geha, Raif S.; Gewies, Andreas; Giese, Thomas; Greil, Johann; Keller, Bärbel; McKinnon, Margaret L.; Neven, Bénédicte; Rozmus, Jacob; Ruland, Jürgen; Snow, Andrew L.; Stepensky, Polina; Warnatz, Klaus

doi:10.1016/j.jaci.2014.06.015

Cited by 120 publications

(107 citation statements)

References 64 publications

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“…In contrast, as shown in mice, CARD11 appears to be essential for thymic development of FoxP3 1 natural regulatory T cells. 40,42,43 Previously reported CARD11-deficient patients lacked regulatory T cells 18,19,37 and we could confirm this in PBMC from P2 and lymph node sections from P1. It is conceivable that absence of regulatory T cells was one factor favoring the occurrence of OS.…”

supporting

confidence: 76%

“…18,19,37 Both of our patients initially had a normal fraction of naïve T cells, and P2 had normal to increased T-cell numbers with a normal Vb repertoire. Moreover, conventional T-cell development, as well as positive and negative selection of thymocytes expressing the MHC class I-restricted HY-TCR transgene, proceeds normally in murine Card11 deficiency.…”

mentioning

confidence: 73%

“…Eczematous dermatitis has been observed in 1 additional patient with CARD11 deficiency 37 and in 2 of 4 patients with mutations in the gene encoding MALT1, 44,45 another member of the CARMA1-BCL10-MALT1 (CBM) signalosome complex. T-cell lymphocytic infiltrations have been reported in the skin biopsies of 2 MALT1-deficient patients, but the clonality of the infiltrates was not further investigated.…”

mentioning

confidence: 99%

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Omenn syndrome associated with a functional reversion due to a somatic second-site mutation in CARD11 deficiency

Fuchs

Rensing‐Ehl

Pannicke

et al. 2015

Blood

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supporting

confidence: 76%

mentioning

confidence: 73%

mentioning

confidence: 99%

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Omenn syndrome associated with a functional reversion due to a somatic second-site mutation in CARD11 deficiency

Fuchs

Rensing‐Ehl

Pannicke

et al. 2015

Blood

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“…In humans and mice, genetic defects in components of the antigen receptor signaling pathway result in immunodeficiency syndromes in which the failure to mount an effective immune response confers enhanced susceptibilities to infection and impaired clearance of pathogens (3,4).…”

mentioning

confidence: 99%

Negative Regulation of CARD11 Signaling and Lymphoma Cell Survival by the E3 Ubiquitin Ligase RNF181

Pedersen

Chan

Jattani

et al. 2016

Molecular and Cellular Biology

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NF-B activation downstream of antigen receptor engagement is a highly regulated event required for lymphocyte activation during the adaptive immune response. The pathway is often dysregulated in lymphoma, leading to constitutive NF-B activity that supports the aberrant proliferation of transformed lymphocytes. To identify novel regulators of antigen receptor signaling to NF-B, we developed bioluminescence resonance energy transfer-based interaction cloning (BRIC), a screening strategy that can detect protein-protein interactions in live mammalian cells in a high-throughput manner. Using this strategy, we identified the RING finger protein RNF181 as an interactor of CARD11, a key signaling scaffold in the antigen receptor pathway. We present evidence that RNF181 functions as an E3 ubiquitin ligase to inhibit antigen receptor signaling to NF-B downstream of CARD11. The levels of the obligate signaling protein Bcl10 are reduced by RNF181 even prior to signaling, and Bcl10 can serve as a substrate for RNF181 E3 ligase activity in vitro. Furthermore, RNF181 limits the proliferation of human diffuse large B cell lymphoma cells that depend upon aberrant CARD11 signaling to NF-B for growth and survival in culture. Our results define a new regulatory checkpoint that can modulate the output of CARD11 signaling to NF-B in both normal and transformed lymphocytes.T he activation of the NF-B transcription factor downstream of antigen receptor engagement is a critical event required for lymphocyte activation during the adaptive immune response (1, 2). In humans and mice, genetic defects in components of the antigen receptor signaling pathway result in immunodeficiency syndromes in which the failure to mount an effective immune response confers enhanced susceptibilities to infection and impaired clearance of pathogens (3, 4).CARD11 is a critical signaling scaffold protein that functions to transmit signals from triggered antigen receptors to the IB kinase (IKK) complex, which inducibly phosphorylates inhibitory IB proteins, leading to their ubiquitinylation and degradation, which allows NF-B heterodimers to stably translocate to the nucleus (5-14). During antigen receptor signaling, CARD11 undergoes a transition from a closed, inactive state to an open, active scaffold that recruits several signaling cofactors into a complex that induces IKK kinase activity. CARD11 is kept inactive prior to receptor engagement by an inhibitory domain (ID) that participates in intramolecular interactions that involve the CARD, LATCH, and coiled-coil (CC) domains (15, 16). Triggering of the T cell receptor (TCR) or B cell receptor (BCR) results in the phosphorylation of the ID on specific serines (17-21), which neutralizes its inhibitory activity and allows the signal-induced recruitment of obligate signaling cofactors to CARD11, including Bcl10, MALT1, TRAF6, IKK␥, and caspase-8 (15). The formation and stability of the CARD11-nucleated multiprotein complex dictate the extent and duration of IKK kinase activity and NF-B activation following antig...

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“…Autosomal recessive mutations in this complex have emerged in recent years as causing immunodeficiency without EDA (Turvey et al 2014).…”

Section: Card11-bcl10-malt1 Complex Immunodeficiencymentioning

confidence: 99%

Hematopoietic stem cell transplantations for primary immune deficiencies associated with NFκB mutations: A review of the literature

Scott

Grunebaum

2017

LymphoSign Journal

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The nuclear factor kappa-light-chain-enhancer of activated B-cells (NFκB) family of transcription factors plays an instrumental role in human immunity and lymphoid organ development. Inherited defects affecting these factors or their regulation are associated with increased susceptibility to infections, as well as non-immune abnormalities. Hematopoietic stem cell transplantations (HSCT) have been shown to correct the immune abnormalities in a few patients with NFκB pathway defects. Here we review the pre-HSCT characteristics, as well as the HSCT and outcome of 35 patients who received HSCT for NFκB defects. Twenty-three patients (65.7%) were reported to have survived HSCT. Survival was higher among patients with X-linked ectodermal dysplasia and immunodeficiency (XL-EDA-ID), and those with CARD11-BCL10-MALT1 (CBM) complex defects, in comparison to patients with autosomal dominant ectodermal dysplasia and immunodeficiency (AD-EDA-ID) and IKBKB defects. Survival following myeloablative conditioning was similar to that after reduced intensity conditioning, although donor cells engraftment and immune reconstitution after HSCT was not complete in some patients. The effects of HSCT on organ dysfunction associated with NFκB defects, such as liver toxicity or bowel inflammation, are still not clear. Earlier identification and transplantation of affected patients, as well as better understanding of the pathogenesis and complications of the different NFκB mutations, might improve outcome of HSCT for specific patient populations. Statement of novelty:This review highlights the current indications, regimens, and outcome of HSCT for inherited defects involving various components of the canonical and non-canonical NFκB pathways.

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The CARD11-BCL10-MALT1 (CBM) signalosome complex: Stepping into the limelight of human primary immunodeficiency

Cited by 120 publications

References 64 publications

Omenn syndrome associated with a functional reversion due to a somatic second-site mutation in CARD11 deficiency

Omenn syndrome associated with a functional reversion due to a somatic second-site mutation in CARD11 deficiency

Negative Regulation of CARD11 Signaling and Lymphoma Cell Survival by the E3 Ubiquitin Ligase RNF181

Hematopoietic stem cell transplantations for primary immune deficiencies associated with NFκB mutations: A review of the literature

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