This Research Topic is the second volume in this series, "Community Series in CARMA Proteins: Playing a Hand of Four CARDs". Please see volume I here.

Nearly 25 years ago, the search began for B-cell lymphoma (BCL)-10 binding partners that connect via homophilic interaction with its N-terminal caspase recruitment domain (CARD) to induce nuclear factor-kappa B (NF-κB) activation. This effort led first to the identification of the protein CARD9. Soon afterwards, similar searches identified CARD10 (aka CARMA3), CARD11 (aka CARMA1) and CARD14 (aka CARMA2), as further BCL10 interactors. These discoveries collectively paved the way for landmark progress in our understanding of NF-κB activation pathways downstream of several cell surface receptors on multiple cell types, focused particularly on antigen receptors on lymphocytes. An additional binding partner, called Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), was also implicated in the CARD-BCL10 pathway. The resulting “CBM” complex has since been recognized as a key node in several signaling cascades leading to activation of NF-κB, c-Jun N-terminal kinase (JNK), and mechanistic target of rapamycin 1 (mTORC1), particularly in immune cells.

Mouse models of genetic deficiencies for each CBM component, provided the first evidence for their critical role in cell signaling. More recently, studies of human lymphoid malignancies and novel genetic disorders have shed further light on their important roles. Both gain- and loss-of-function mutations have been identified, establishing these CARMA/CARD proteins as key regulators of proliferation and differentiation of immune and non-immune cells, and linking them to human disease. According to the genetic defect involved, dysregulation of CARMA/CARD pathways can lead to a broad spectrum of immune disorders, including severe immune deficiencies, lymphoproliferative disorders, psoriasis and atopy.

The aim of this Research Topic is to summarize our current understanding of CARMA/CARD protein biology, including updates from recent insights. More specifically, we will focus on CARD9 and the CARMA proteins CARD10, CARD11 and CARD14, from genetic, disease and signaling perspectives. This Research Topic will also highlight emerging, important open questions to guide future research efforts.

We welcome the submission of Original Research, Review and Mini-Review articles that cover, but are not limited to, the following topics:

1. Role of CARMA / CARD proteins in signaling pathways in immune and non-immune cells.
2. Role of CARMA / CARD proteins in immune cell physiology, e.g. survival, proliferation and differentiation.
3. The involvement of dysregulated CARMA / CARD pathways in disorders of the immune system including severe immune deficiencies, atopy/allergy, autoimmunity, and lymphoproliferative diseases.
4. Therapeutic targeting of CARMA / CARD pathways for the treatment of immune-related diseases.

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Frontiers in Immunology

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