9.A.35 The Peptide Translocating Syndecan (Syndecan) Family

Syndecans are transmembrane heparan sulfate proteoglycans. They are implicated in the binding of extracellular matrix components and growth factors. Syndecan is made as a precursor with a hydrophobic N-terminal leader peptide and a strongly hydrophobic C-terminal TMS which presumably anchors the protein in the membrane.  Syndecan-4 and beta1 integrin protein levels and their localization in costameric structures are regulated by electrical activity by a mechanism that influences the adhesion properties of skeletal myotubes during differentiation (Ugarte et al. 2010). Multiple dimerizing motifs are present at different locations in the protein, including in the transmembrane domain, and these modulate the homo- and hetero-dimerization of syndecan (Chen et al. 2021). The conformations, interactions and functions of intrinsically disordered external domains of syndecans have been reviewed (Ricard-Blum and Couchman 2023). Syndecans link the cytoskeleton to calcium channels of the transient receptor potential class (TC# 1.A.4), compatible with roles as mechanosensors. In turn, syndecans influence actin cytoskeletal organization to impact ion transport, motility, adhesion and the extracellular matrix environment (Ricard-Blum and Couchman 2023).

Cell-penetrating peptides (CPPs) are short peptides capable of translocating across the plasma membrane of live cells and transporting conjugated compounds intracellularly. The first model cationic CPPs to be discovered were penetratin and TAT. CPPs may enter cells by mediation using a surface receptor. Letoha et al. (2010) reported that syndecan-4, the universally expressed isoform of the syndecan family of transmembrane proteoglycans, binds and mediates transport of the three most frequently utilized cationic CPPs (penetratin, octaarginine and TAT) into the cells. Quantitative uptake studies and mutational analyses demonstrate that attachment of the cationic CPPs is mediated by specific interactions between the heparan sulfate chains of syndecan-4 and the CPPs. Protein kinase C alpha is also involved in uptake. The data presented by Letoha et al. (2010) provide direct evidence for the receptor-mediated uptake of cationic CPPs. ESCRT-to-membrane coupling via ALIX/syntenin/syndecan-4 is required for completion of cytokinesis (Addi et al. 2020).

Syndecans, the evolutionarily conserved family of transmembrane proteoglycans, facilitate the cellular entry of SARS-CoV-2 (Hudák et al. 2021). Among syndecans, the lung abundant syndecan-4 is the most efficient in mediating SARS-CoV-2 uptake. The S1 subunit of the SARS-CoV-2 spike protein plays a dominant role in the virus's interactions with syndecans. Besides the polyanionic heparan sulfate chains, other parts of the syndecan ectodomain, such as the cell-binding domain, also contribute to the interaction with SARS-CoV-2. During virus internalization, syndecans colocalize with ACE2, suggesting a jointly shared internalization pathway. Both ACE2 and syndecan inhibitors exhibit significant efficacy in reducing the cellular entry of SARS-CoV-2, thus supporting the complex nature of internalization (Hudák et al. 2021).

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