Syntenins at the crossroads of host-virus interactions

Syntenin is a multifunctional PDZ-domain adaptor protein that orchestrates membrane trafficking, cytoskeletal remodeling, and exosome biogenesis. Initially identified as a syndecan-binding molecule, syntenin has since emerged as a central hub connecting membrane receptors to intracellular signaling pathways that regulate adhesion, motility, immune signaling, and cellular plasticity. While extensively studied in cancer and neural development, recent discoveries reveal that a wide range of viruses exploit syntenin to facilitate their replication, assembly, or dissemination. This review consolidates current evidence across diverse viral infections to elucidate the molecular mechanisms underlying the interaction between syntenin and viruses. Coronaviruses utilize syntenin to link PDZ-binding motifs to p38 MAPK-driven inflammation and endosomal entry. Papillomaviruses and Epstein-Barr virus hijack the CD63-syntenin-ALIX complex to control vesicle-mediated trafficking. Hepatitis C virus employs it to secrete E2-coated, antibody-resistant exosomes. Dengue virus harnesses its mosquito homolog AeSyntenin to package sfRNA for transmission. Human T-cell leukemia virus type 1 employs its Tax-1 oncoprotein to bind the PDZ domains of syntenin, remodel extracellular vesicle cargo, and promote viral spread. In contrast, during human immunodeficiency virus infection, syntenin restricts viral fusion at the plasma membrane, though the nucleocapsid mimics its PDZ tandem to promote virion release. Collectively, these findings establish syntenin as a dynamic regulator at the host-virus interface, capable of exerting both proviral and antiviral effects. Emerging pharmacological strategies targeting syntenin PDZ domains further underscore its potential as a broad-spectrum, host-directed antiviral target.