{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n CXADR, which encodes the coxsackievirus and adenovirus receptor (CAR), is emerging as a multifunctional transmembrane protein that not only serves as a primary viral attachment receptor but also plays important roles in cell–cell adhesion and signaling across diverse tissues. In polarized epithelia, CAR is concentrated at tight junctions where it engages in specific protein–protein interactions with PDZ‐domain partners—such as MUPP1 and LNX—to promote the assembly and stability of intercellular junctions, while its binding with viral capsid proteins (e.g., adenovirus fiber) triggers intracellular signaling cascades (see."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, distinct CAR isoforms contribute to tissue-specific functions. In airway epithelia, for example, the apically localized isoform CAR(Ex8) enhances adenoviral infection from the luminal surface—contrasting with the basolateral CAR(Ex7) and highlighting isoform‐dependent regulation of viral tropism."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the cardiovascular system, CAR is found at the intercalated discs of cardiomyocytes where it is essential for proper electrical conduction and heart development. Studies using conditional knockout models have demonstrated that CAR deficiency leads to conduction block, improper junction formation, and even embryonic lethality, underscoring its critical role in cardiac morphogenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n CAR also influences viral biodistribution. Expression of CAR on erythrocytes, for instance, can prolong the in vivo half‐life of adenovirus particles and diminish liver transduction, while in neurons CAR facilitates efficient adenoviral endocytosis and axonal transport."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the reproductive system, CAR is expressed in male germ cells—localizing to distinct regions of the acrosome of spermatids and spermatozoa—and interacts with other junctional proteins such as JAM‐C, suggesting a role in spermatid adhesion and perhaps male fertility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, recent findings indicate that CAR can function as a signaling receptor in the immune system by binding to junctional partners like JAML, which in turn recruits phosphoinositide 3‐kinase and modulates immune cell responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": " In addition, the ability of CAR to trigger conformational changes in viral capsids is critical for virus uncoating and successful infection"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": ", and its structural and functional similarities with related immunoglobulin superfamily members (e.g., IGSF11) underscore a conserved role in cell adhesion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies demonstrate that CXADR is a key determinant at the crossroads of viral entry, tissue morphogenesis, and intercellular signaling in multiple organ systems. Its diverse functions in epithelial barrier integrity, cardiac conduction, neuronal trafficking, and reproductive biology—as well as its role in modulating immune responses—highlight its importance as a therapeutic target in viral diseases, gene therapy, and beyond."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}, {"type": "fg_f", "ref": "15"}, {"type": "fg_f", "ref": "5"}, {"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Simon N Waddington, John H McVey, David Bhella, et al. 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