The F protein at the envelope of the respiratory syncytial virus (RSV) binds to NCL (nucleolin) presented on the apical surface of host cells. The RSV infection rate decreases when the RSV preparation is pre-incubated with soluble NCL, when host cells are pre-treated with an anti-NCL antibody, or when NCL level in host cells is knocked down by RNAi. NCL thus serves as an RSV entry co-receptor (Tayyari et al. 2011). NCL is predominantly a nuclear protein. Binding of the G-protein of RSV to the CX3CR1 receptor expressed on the surface of normal human bronchial epithelial (NHBE) cells has been shown to induce downstream signaling that results in changes in gene expression. For example, NCL is upregulated and cilium-associated genes including CC2D2A and CFAP221 (PCDP1) are downregulated (Anderson et al. 2021). F protein has been reported to bind to Insulin-like growth factor receptor 1 (IGFR1), which triggers a signaling cascade that activates Protein kinase C-zeta (PRKCZ). Activated PRKCZ promotes relocalization of NCL from the nucleus to the plasma membrane, where it can bind to the F protein and act as a co-receptor for RSV entry into the host cell (Griffiths et al. 2020). NCL has been reported to be a direct substrate of PRKCZ (Zhou et al. 1997), but this relationship has not been further investigated. Extranuclear NCL, including plasma membrane-associated NCL, undergoes glycosylation (Carpentier et al. 2005, Aldi et al. 2009; Losfeld et al. 2009; Losfeld et al. 2011), but it is uncertain what role this plays in trafficking to the plasma membrane and RSV binding. Binding of ligands to the plasma membrane-associated NCL may induce Ca2+ entry into the cells (Losfeld et al. 2009). The glycine arginine rich (GAR) domain of NCL is involved in regulation of subcellular localization of NCL via protein-protein interactions with a kinesin light chain, which may regulate NCL trafficking, and via protein-protein interactions with plasma membrane components (Doron-Mandel et al. 2021).

The role of NCL in the entry of RSV, other viruses, and bacteria is reviewed in Tonello et al. 2022.