Alternative splicing generates a novel CARD9 isoform

CARD9 is a key adaptor protein involved in innate immune signaling and plays a vital role in defending the host against fungal, bacterial, and viral infections. Its activation triggers downstream pathways that promote cytokine production and immune cell recruitment. Deficiency or dysfunction of CARD9 can impair these responses, thereby increasing the host's susceptibility to infections. In this study, we have identified a novel human CARD9 transcript (CARD9-N) through an integrated bioinformatics and molecular biology approach. This isoform features a distinct N-terminal region due to the inclusion of a novel sequence (N3') upstream of coding exon E3 and the exclusion of coding exons E1 and E2. Structural and functional characterization have revealed significant differences between CARD9 and CARD9-N, including variations in molecular weight, isoelectric point, phosphorylation sites, and dimerization stability. Notably, the absence of the CARD domain in CARD9-N is expected to impair canonical functions, yet it may activate immune responses due to reduced dimerization-driven autoinhibition. These findings highlight the functional diversity of CARD9 isoforms and provide a foundation for further studies to explore their roles in immune regulation and immune-related disorders.