Nucleolin: a cell portal for viruses, bacteria, and toxins

Abstract

The main localization of nucleolin is the nucleolus, but this protein is present in multiple subcellular sites, and it is unconventionally secreted. On the cell surface, nucleolin acts as a receptor for various viruses, some bacteria, and some toxins. Aim of this review is to discuss the characteristics that make nucleolin able to act as receptor or co-receptor of so many and different pathogens. The important features that emerge are its multivalence, and its role as a bridge between the cell surface and the nucleus. Multiple domains, short linear motifs and post-translational modifications confer and modulate nucleolin ability to interact with nucleic acids, with proteins, but also with carbohydrates and lipids. This modular multivalence allows nucleolin to participate in different types of biomolecular condensates and to move to various subcellular locations, where it can act as a kind of molecular glue. It moves from the nucleus to the cell surface and can accompany particles in the reverse direction, from the cell surface into the nucleus, which is the destination of several pathogens to manipulate the cell in their favour.

Inhibition of Respiratory Syncytial Virus Infection by Small Non-Coding RNA Fragments

“…Mapping the causality between the antiviral effect of sncRNAs to nucleolin and RSV infection has proven to be difficult, as knocking down nucleolin significantly reduces RSV infection, which confirms that nucleolin is indeed a receptor for RSV [ 11 , 31 ]. Furthermore, as nucleolin is an essential protein involved in many cellular processes such as the proliferation, transcriptional regulation, stability and transportation of mRNA, previous studies have shown that knocking out nucleolin is lethal to cells [ 32 , 33 ], precluding the possibility of conducting such experiments to show that the functional mechanism of ssONs is blocking nucleolin. As nucleolin is the only established functional receptor for RSV to date, it would be difficult to find other interaction partners for sncRNAs in relation to RSV infection.…”

Quantum Dot-Based Screening Identifies F3 Peptide and Reveals Cell Surface Nucleolin as a Therapeutic Target for Rhabdomyosarcoma

“…Surface expression of nucleolin has been reported in many different cancer types, and its involvement in cancer has been extensively studied (reviewed in [ 78 , 79 , 80 , 81 , 82 ]). At the cell surface, nucleolin can act as a receptor for various viruses [ 83 ]. The detailed mechanism of internalization and subcellular fate of F3-functionalized nanoparticles has been intensively studied using polyacrylamide nanocarriers (NC) and comparing targeted NC, non-targeted NC, and F3 peptide alone.…”

Secretory Phospholipases A2, from Snakebite Envenoming to a Myriad of Inflammation Associated Human Diseases—What Is the Secret of Their Activity?

“…In addition to HSPGs, two group II sPLA2s, the human one and a PLA2-like myotoxin, interact with two proteins, nucleolin (NCL) and vimentin (VIM), known for their ability to establish multiple molecular interactions both inside the cell, where they are normally found, and on the cell surface, where they are secreted by unconventional mechanisms [ 36 , 68 ]. On the cell surface, NCL and VIM interact with different membrane receptors, forming complexes that mediate the internalization of different types of viruses or other pathogens and proteins [ 71 , 72 ]. Membrane proteins with which NCL and VIM interact include integrins alpha 3, alpha 4, beta 1, and beta 3 (ITGA4, ITGA6, ITGB1, and ITGB3), the epidermal growth factor receptor (EGFR), and glypican-1 (GPC-1), all identified as group II sPLA2 receptors [ 34 ] ( Figure 3 ).…”