CARD14 signalosome formation is associated with its endosomal relocation and mTORC1-induced keratinocyte proliferation.

Rare mutations in CARD14 promote psoriasis by inducing CARD14-BCL10-MALT1 complexes that activate NF-κB and MAP kinases. Here, the downstream signalling mechanism of the highly penetrant CARD14E138A alteration is described. In addition to BCL10 and MALT1, CARD14E138A associated with several proteins important in innate immune signalling. Interactions with M1-specific ubiquitin E3 ligase HOIP, and K63-specific ubiquitin E3 ligase TRAF6 promoted BCL10 ubiquitination and were essential for NF-κB and MAP kinase activation. In contrast, the ubiquitin binding proteins A20 and ABIN1, both genetically associated with psoriasis development, negatively regulated signalling by inducing CARD14E138A turnover. CARD14E138A localized to early endosomes and was associated with the AP2 adaptor complex. AP2 function was required for CARD14E138A activation of mTOR complex 1 (mTORC1), which stimulated keratinocyte metabolism, but not for NF-κB nor MAP kinase activation. Furthermore, rapamycin ameliorated CARD14E138A-induced keratinocyte proliferation and epidermal acanthosis in mice, suggesting that blocking mTORC1 may be therapeutically beneficial in CARD14-dependent psoriasis.

Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-κB activation.

Inherited and de novo mutations in the CARD14 gene promote the development of psoriasis, an inflammatory disease of the skin. Caspase recruitment domain-containing protein 14 (CARD14) is a member of the CARMA protein family that includes the structurally related CARD11 adaptor that mediates NF-κB activation by antigen receptors. We investigated the mechanism by which CARD14 mutation in psoriasis activates NF-κB. In contrast with wild-type CARD14, CARD14(E138A) and CARD14(G117S) psoriasis mutants interacted constitutively with BCL10 and MALT1, and triggered BCL10- and MALT1-dependent activation of NF-κB in keratinocytes. These alterations disrupted the inhibitory effect of the CARD14 linker region (LR) on NF-κB activation by facilitating BCL10 binding. Therefore, psoriasis mutations activated CARD14 by a mechanism analogous to oncogenic CARD11 mutations in non-Hodgkin B cell lymphomas. CARD14(E138A) also stimulated MALT1 paracaspase activity and activated both ERK1/2 and p38α MAP kinases. Inhibition of MALT1 with mepazine reduced CARD14(E138A)-induced expression of specific psoriasis-associated transcripts in keratinocytes. Our results establish the mechanism whereby gain-of-function CARD14 variants, which induce psoriatic disease in affected individuals, activate pro-inflammatory signalling.

Laparoscopic right hemicolectomy with intracorporeal versus extracorporeal anastamosis: a comparison of short-term outcomes.

BACKGROUND: There is wide variation among laparoscopic colon resection techniques, including the approach for mobilization and the extent of intracorporal vessel ligation, bowel division or anastamosis. We compared the short-term outcomes of laparoscopic right hemicolectomy (LRHC) with intracorporeal (IA) versus extracorporeal (EA) anastamosis. METHODS: We retrospectively reviewed all elective laparoscopic right hemicolectomies performed at St. Joseph's Hospital between January 2008 and September 2009 and compared the demographic, pathologic, operative and outcome data. RESULTS: Fifty LRHCs were completed during the study period: 21 IA and 29 EA. The groups were similar in age, sex, body mass index, American Society of Anesthesiologists score, previous laparotomy and preoperative invasive pathology. There was no difference between IA and EA in mean duration of surgery (170 v. 181 min, p = 0.78), estimated blood loss (14 v. 42 mL, p = 0.15), perioperative blood transfusions (5% v. 14%, p = 0.29), in-hospital morbidity (33% v. 41%, p = 0.56), out-of-hospital morbidity (19% v. 31% p = 0.34), emergency department visits (10% v. 17%, p = 0.16) or 30-day readmissions (5% v. 7%, p = 0.75). There was 1 anastamotic leak in each group and no perioperative deaths. Median length of stay was significantly shorter for IA (4 v. 5 d, p = 0.05). There were 6 extraction site hernias with EA and none with IA (p = 0.026). CONCLUSION: Laparoscopic right hemicolectomy with IA has the advantage of a less hernia-prone Pfannenstiel extraction site, faster recovery and shorter stay in hospital EA.

CONTEXTE: Il existe énormément de variations entre les techniques d'exérèse du côlon par laparascopie, y compris en ce qui concerne l'approche adoptée pour la mobilisation et l'étendue de la ligature vasculaire intracorporelle, la séparation du côlon ou l'anastomose. Nous avons comparé les résultats à court terme de l'hémicolectomie droite laparascopique (HDL) avec anastomose intracorporelle (AI) à ceux de l'HDL avec anastomose extracorporelle (AE). MÉTHODES: Nous avons effectué une analyse rétrospective de toutes les hémicolectomies droites laparascopiques non urgentes pratiquées à l'hôpital St. Joseph entre janvier 2008 et septembre 2009, et comparé les données démographiques, pathologiques et opératoires et les données sur les résultats. RÉSULTATS: Cinquante HDL ont été pratiquées au cours de l'étude : 21 avec AI et 29 avec AE. Les groupes de patients étaient comparables pour ce qui était de l'âge, du sexe, de l'indice de masse corporelle, du score de l'American Society of Anesthesiologists, des antécédents de laparatomie et de la pathologie invasive préopératoire. Aucune différence n'a été observée entre l'AI et l'AE pour ce qui est de la durée moyenne de l'intervention chirurgicale (170 c. 181 min, p = 0,78), de la perte de sang estimée (14 c. 42 mL, p = 0,15), des transfusions sanguines péri-opératoires (5 % c. 14 %, p = 0,29), de la morbidité hospitalière (33 % c. à 41 %, p = 0,56), de la morbidité extra-hospitalière (19 % c. 31 %, p = 0,34), des admissions à l'urgence (10 % c. 17 %, p = 0,16) ou des réadmissions à l'hôpital dans les 30 jours (5 % c. 7 %, p = 0,75). On a signalé 1 fuite anastomique dans chaque groupe, mais aucun décès péri-opératoire. La durée médiane de l'hospitalisation était significativement plus courte pour les AI (4 c. 5 j, p = 0,05). Il y a eu 6 hernies au point d'extraction pour les AE, mais aucune pour les AI (p = 0,026). CONCLUSION: L'hémicolectomie droite laparascopique avec AI a l'avantage de réduire le risque d'hernie au point d'extraction après incision de Pfannenstiel, d'accélérer le rétablissement de réduire la durée de l'hospitalisation.

Bioinformatic analysis of molecular characteristics and oncogenic features of CARD14 in human cancer.

Aberrant caspase recruitment domain family member 14 (CARD14) signaling has been strongly associated with inflammatory skin conditions. CARD14 acts as a scaffold protein, ultimately activating the transcription factor NF-KB. Although primarily studied in the context of inflammation, recent research has suggested its potential implications in tumorigenesis. In this study, we gathered The Cancer Genome Atlas (TCGA) tumor data to gauge the involvement of CARD14 in cancer, including genetic alterations, expression patterns, survival correlations, immune cell infiltration and functional interactions across diverse cancer types. We found heightened CARD14 expression in most tumors and there was a significant correlation between CARD14 expression and the prognosis of patients for certain tumors. For instance, patients with higher CARD14 expression had a better prognosis in sarcoma, lung, cervix and head and neck cancers. Moreover, CARD14 expression positively correlated with neutrophil infiltration in most of the cancer types analyzed. Finally, enrichment analysis showed that epithelial development and differentiation pathways were involved in the functional mechanism of CARD14. Our results show that CARD14 may have the potential to become a prognostic biomarker in several cancers, hence, further prospective studies will be required for its validation.