The role of the CBM complex in allergic inflammation and disease

DeVore, Stanley B.; Hershey, Gurjit K. Khurana

doi:10.1016/j.jaci.2022.06.023

Cited by 12 publications

(11 citation statements)

References 235 publications

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“…The E138 allelic series showed that the PRP mutation E138K was a stronger activator than the two psoriasis-associated mutations E138A and E138del, in line with the suggested correlation between mutation strength and disease phenotype [48]. At this moment, no association has been made between a disease condition and activating mutations in CARD10 [27]. However, several germline mutations in the CARD10 CC domain have been found associated to diseases, such as primary open angle glaucoma (POAG), or as a single case of autoimmunity / immunodeficiency (R420C) [41], [42].…”

Section: Using the Chimeric Franken-card9 Constructs To Analyze Activ...mentioning

confidence: 66%

“…At this moment, no association has been made between a disease condition and activating mutations in CARD10 [27]. However, several germline mutations in the CARD10 CC domain have been found associated to diseases, such as primary open angle glaucoma (POAG), or as a single case of autoimmunity / immunodeficiency (R420C) [41], [42].…”

Section: Resultsmentioning

confidence: 99%

“…An advantage with these constructs is that they will look and act approximately the same except for the sequence that has been swapped, so there should be fewer artifacts from deletion-induced spontaneous activation or other structural changes. Up until now, only naturally occurring activating germ line mutations have been described in CARD11 (causing B cell lymphoma and BENTA) and CARD14 (causing psoriasis and PRP) within the CARD-CC family [27]. Activating mutations are typically dominant, and will thus usually be less frequent than recessive loss-of-function mutations if detrimental.…”

Section: Discussionmentioning

confidence: 99%

“…1b), which may be part of the auto-inhibition mechanism. Since, to our knowledge, no germ-line activating mutations have been found or described in CARD9 [27], we investigated natural potentially activating substitutions from human sequence data in Uniprot [56]. One of the most striking candidate germ line activating CARD9 mutations is a natural CARD9 variant causing the very rare CARD9 G111E mutation (rs371695061), corresponding to the BENTA-associated CARD11 G123D mutation (rs571517554) -which is more severe than the previously mentioned CARD11 G123S BENTA mutation [47].…”

Section: Sequence Alignment Can Identify Activating Mutations Transfe...mentioning

confidence: 99%

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Chimeric and mutant CARD9 constructs enable analyses of conserved and diverged autoinhibition mechanisms in the CARD-CC protein family

Staal

Driege

Gaever

et al. 2023

Preprint

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CARD9, -10, -11 and -14 all belong to the CARD-coiled coil (CC) protein family and originated from a single common ancestral protein early in vertebrate evolution. All four proteins form CARD-CC/BCL10/MALT1 (CBM) complexes leading to NF-kappaB activation after upstream phosphorylation by various protein kinase C (PKC) isoforms. CBM complex signaling is critical for innate and adaptive immunity, but aberrant activation can cause autoimmune or autoinflammatory diseases, or be oncogenic. CARD9 is the only family member that has retained the original domain organization. The other family members have been fused to a C-terminal ZO-1/Dlg5-like MAGUK domain, forming the CARMA sub-family. CARD9 shows a superior auto-inhibition with very low spontaneous activity when overexpressed in HEK293T cells. In contrast, the poor auto-inhibition of other CARD-CC family proteins, especially CARD10 (CARMA3) and CARD14 (CARMA2), is hampering characterization of upstream activators or activating mutations in overexpression studies. We grafted different domains from CARD10, -11 and 14 on CARD9 to generate chimeric Franken-CARD9 backbones for functional characterization of activating mutants using NF-κB reporter gene activation in HEK293T cells as readout. This revealed that most of the poor auto-inhibition of CARD10 and CARD14 can be mapped to the CARD10 LATCH and CARD14 CARD domains, respectively. CARD11 (CARMA1) activity was not further reduced by grafting on Franken-CARD9 backbones. The Franken-CARD9 approach was subsequently validated by using several known disease-associated mutations in CARD10 and CARD14, and additional screening allowed us to identify several novel activating natural variants in human CARD9 and CARD10. Using Genebass as a resource of exome-based disease association statistics, we found that activated alleles of CARD9 correlate with irritable bowel syndrome (IBS), constipation, arthritis, fibromyalgia, insomnia, anxiety and depression, which can occur as comorbidities.

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Section: Using the Chimeric Franken-card9 Constructs To Analyze Activ...mentioning

confidence: 66%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Sequence Alignment Can Identify Activating Mutations Transfe...mentioning

confidence: 99%

See 2 more Smart Citations

Chimeric and mutant CARD9 constructs enable analyses of conserved and diverged autoinhibition mechanisms in the CARD-CC protein family

Staal

Driege

Gaever

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…At this moment, no association has been made between a disease condition and activating mutations in CARD10 [27]. However, several germline mutations in the CARD10 CC domain have been found associated to diseases, such as primary openangle glaucoma (POAG), or as a single case of autoimmunity/immunodeficiency (R420C) [39,40].…”

Section: Using the Chimeric Card9 Constructs To Analyze Activating Mu...mentioning

confidence: 99%

Chimeric and mutant CARD9 constructs enable analyses of conserved and diverged autoinhibition mechanisms in the CARD‐CC protein family

Staal,

Driege,

Van Gaever

et al. 2023

The FEBS Journal

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Caspase recruitment domain‐containing protein (CARD)9, CARD10, CARD11, and CARD14 all belong to the CARD‐coiled coil (CC) protein family and originated from a single common ancestral protein early in vertebrate evolution. All four proteins form CARD‐CC/BCL10/MALT1 (CBM) complexes leading to nuclear factor‐kappa‐B (NF‐κB) activation after upstream phosphorylation by various protein kinase C (PKC) isoforms. CBM complex signaling is critical for innate and adaptive immunity, but aberrant activation can cause autoimmune or autoinflammatory diseases, or be oncogenic. CARD9 shows a superior auto‐inhibition compared with other CARD‐CC family proteins, with very low spontaneous activity when overexpressed in HEK293T cells. In contrast, the poor auto‐inhibition of other CARD‐CC family proteins, especially CARD10 (CARMA3) and CARD14 (CARMA2), is hampering characterization of upstream activators or activating mutations in overexpression studies. We grafted different domains from CARD10, 11, and 14 on CARD9 to generate chimeric CARD9 backbones for functional characterization of activating mutants using NF‐κB reporter gene activation in HEK293T cells as readout. CARD11 (CARMA1) activity was not further reduced by grafting on CARD9 backbones. The chimeric CARD9 approach was subsequently validated by using several known disease‐associated mutations in CARD10 and CARD14, and additional screening allowed us to identify several previously unknown activating natural variants in human CARD9 and CARD10. Using Genebass as a resource of exome‐based disease association statistics, we found that activated alleles of CARD9 correlate with irritable bowel syndrome (IBS), constipation, osteoarthritis, fibromyalgia, insomnia, anxiety, and depression, which can occur as comorbidities.

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Targeting of MALT1 May Improve Functional Recovery and Attenuate Microglia M1 Polarization-Mediated Neuroinflammation During Spinal Cord Injury

Zhang

Chen

et al. 2023

Mol Neurobiol

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The role of the CBM complex in allergic inflammation and disease

Cited by 12 publications

References 235 publications

Chimeric and mutant CARD9 constructs enable analyses of conserved and diverged autoinhibition mechanisms in the CARD-CC protein family

Chimeric and mutant CARD9 constructs enable analyses of conserved and diverged autoinhibition mechanisms in the CARD-CC protein family

Chimeric and mutant CARD9 constructs enable analyses of conserved and diverged autoinhibition mechanisms in the CARD‐CC protein family

Targeting of MALT1 May Improve Functional Recovery and Attenuate Microglia M1 Polarization-Mediated Neuroinflammation During Spinal Cord Injury

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