CARD14, also known as CARMA2, is an intracellular scaffold protein predominantly expressed in keratinocytes [1,2,3,6]. It plays a crucial role in regulating pro-inflammatory gene expression by forming a signaling complex with BCL10 and the paracaspase MALT1, which activates NF-κB and MAPK signaling pathways [1,2,3,4,6]. This signaling is significant for innate immune defense at the epidermal barrier and maintaining tissue homeostasis [2,6]. Genetic mouse models have been valuable in studying CARD14's function [4,5].

In a CARD14E138A knock-in mouse model, heterozygous expression of the mutation rapidly induced skin acanthosis, immune cell infiltration, and expression of psoriasis-associated pro-inflammatory genes. Homozygous expression led to more extensive skin inflammation and a severe systemic disease resembling acute exacerbations of generalized pustular psoriasis (GPP) [5]. This shows that CARD14E138A-induced skin inflammation and systemic disease are independent of adaptive immune cells, ameliorated by blocking TNF, and induced by CARD14E138A signaling only in keratinocytes [5]. Additionally, in another study, rapamycin, which blocks mTORC1, ameliorated CARD14E138A-induced keratinocyte proliferation and epidermal acanthosis in mice, suggesting that blocking mTORC1 may be therapeutically beneficial in CARD14-dependent psoriasis [4].

In conclusion, CARD14 is essential for regulating inflammation and epidermal homeostasis through its signaling in keratinocytes. The use of mouse models, such as the CARD14E138A knock-in model, has provided key insights into the role of CARD14 in psoriasis and related skin diseases, highlighting potential therapeutic targets like mTORC1 and TNF for treating these conditions [4,5].

References:

1. Van Nuffel, Elien, Schmitt, Anja, Afonina, Inna S, Beyaert, Rudi, Hailfinger, Stephan. 2016. CARD14-Mediated Activation of Paracaspase MALT1 in Keratinocytes: Implications for Psoriasis. In The Journal of investigative dermatology, 137, 569-575. doi:10.1016/j.jid.2016.09.031. https://pubmed.ncbi.nlm.nih.gov/27939769/

2. Zotti, Tiziana, Polvere, Immacolata, Voccola, Serena, Vito, Pasquale, Stilo, Romania. 2018. CARD14/CARMA2 Signaling and its Role in Inflammatory Skin Disorders. In Frontiers in immunology, 9, 2167. doi:10.3389/fimmu.2018.02167. https://pubmed.ncbi.nlm.nih.gov/30319628/

3. Mellett, Mark. 2020. Regulation and dysregulation of CARD14 signalling and its physiological consequences in inflammatory skin disease. In Cellular immunology, 354, 104147. doi:10.1016/j.cellimm.2020.104147. https://pubmed.ncbi.nlm.nih.gov/32593012/

4. O'Sullivan, Paul A, Aidarova, Aigerim, Afonina, Inna S, Bowcock, Anne M, Ley, Steven C. . CARD14 signalosome formation is associated with its endosomal relocation and mTORC1-induced keratinocyte proliferation. In The Biochemical journal, 481, 1143-1171. doi:10.1042/BCJ20240058. https://pubmed.ncbi.nlm.nih.gov/39145956/

5. Manils, Joan, Webb, Louise V, Howes, Ashleigh, Bowcock, Anne M, Ley, Steven C. 2020. CARD14E138A signalling in keratinocytes induces TNF-dependent skin and systemic inflammation. In eLife, 9, . doi:10.7554/eLife.56720. https://pubmed.ncbi.nlm.nih.gov/32597759/

6. Israel, Laura, Mellett, Mark. 2018. Clinical and Genetic Heterogeneity of CARD14 Mutations in Psoriatic Skin Disease. In Frontiers in immunology, 9, 2239. doi:10.3389/fimmu.2018.02239. https://pubmed.ncbi.nlm.nih.gov/30386326/