Role of Extracellular Vimentin in Cancer-Cell Functionality and Its Influence on Cell Monolayer Permeability Changes Induced by SARS-CoV-2 Receptor Binding Domain.

Divyendu Goud Thalla,Philipp Jung,Franziska Lautenschläger,Markus Bischoff

doi:10.3390/ijms22147469

Abstract

The cytoskeletal protein vimentin is secreted under various physiological conditions. Extracellular vimentin exists primarily in two forms: attached to the outer cell surface and secreted into the extracellular space. While surface vimentin is involved in processes such as viral infections and cancer progression, secreted vimentin modulates inflammation through reduction of neutrophil infiltration, promotes bacterial elimination in activated macrophages, and supports axonal growth in astrocytes through activation of the IGF-1 receptor. This receptor is overexpressed in cancer cells, and its activation pathway has significant roles in general cellular functions. In this study, we investigated the functional role of extracellular vimentin in non-tumorigenic (MCF-10a) and cancer (MCF-7) cells through the evaluation of its effects on cell migration, proliferation, adhesion, and monolayer permeability. Upon treatment with extracellular recombinant vimentin, MCF-7 cells showed increased migration, proliferation, and adhesion, compared to MCF-10a cells. Further, MCF-7 monolayers showed reduced permeability, compared to MCF-10a monolayers. It has been shown that the receptor binding domain of SARS-CoV-2 spike protein can alter blood–brain barrier integrity. Surface vimentin also acts as a co-receptor between the SARS-CoV-2 spike protein and the cell-surface angiotensin-converting enzyme 2 receptor. Therefore, we also investigated the permeability of MCF-10a and MCF-7 monolayers upon treatment with extracellular recombinant vimentin, and its modulation of the SARS-CoV-2 receptor binding domain. These findings show that binding of extracellular recombinant vimentin to the cell surface enhances the permeability of both MCF-10a and MCF-7 monolayers. However, with SARS-CoV-2 receptor binding domain addition, this effect is lost with MCF-7 monolayers, as the extracellular vimentin binds directly to the viral domain. This defines an influence of extracellular vimentin in SARS-CoV-2 infections.

Highlights

Vimentin is a cytoskeletal filament of the family of intermediate filaments that has a vital role in cell migration, adhesion, and signaling due to its interactions with various proteins [1]
Vimentin is secreted by various cell types, such as macrophages, astrocytes, neutrophils, monocytes, apoptotic lymphocytes, and endothelial cells [3,5,6,7,8]
As there is the need for ways to interfere with the entry of SARS-CoV-2 into human cells, this secreted extracellular vimentin might represent a valuable target for the modulation of SARS-CoV-2 entry into cells. These investigations were carried out using cells derived from human breast epithelium, as the control MCF-10a non-tumorigenic cells and the MCF-7 cancer cells, both of which express insulinlike growth factor-1 receptor (IGF-1R)

Summary

Introduction

Vimentin is a cytoskeletal filament of the family of intermediate filaments that has a vital role in cell migration, adhesion, and signaling due to its interactions with various proteins [1]. Vimentin is involved in cell physiology, inflammation, wound healing, and immune responses [2]. Its involvement in these cellular functions is believed to be through its dynamic phosphorylation. Vimentin is secreted by various cell types, such as macrophages, astrocytes, neutrophils, monocytes, apoptotic lymphocytes, and endothelial cells [3,5,6,7,8]. This extracellular vimentin can either remain bound to the cell surface (i.e., surface vimentin) or it can be secreted in an unbound form in the extracellular matrix (i.e., secreted vimentin)

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