Integrin-mediated cell adhesion requires extracellular disulfide exchange regulated by protein disulfide isomerase

Nurit Rosenberg*, Ronit Mor-Cohen, Vera Hazan Sheptovitsky, Olga Romanenco, Oded Hess, Judith Lahav

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Cell adhesion to extracellular matrix, mediated by integrin receptors, is crucial for cell survival. Receptor-ligand interaction involves conformational changes in the integrin by a mechanism not fully elucidated. In addition to several direct evidence that there is disulfide re-arrangement of integrins, we previously demonstrated a role for extracellular thiols and protein disulfide isomerase (PDI)in integrin-mediated functions using platelets as model system. Exploring the possible generality of this mechanism, we now show, using three different nucleated cells which depend on adhesion for survival, that non-penetrating blockers of free thiols inhibit α2β1 and α5β1 integrin-mediated adhesion and that disulfide exchange takes place in that process. Inhibiting extracellular PDI mimics thiol blocking. Transfection with WT or enzymatically inactive PDI increased their membrane expression and enhanced cell adhesion, suggesting that PDI level is a limiting factor and that the chaperone activity of the enzyme contributes to adhesion. Exogenously added PDI also enhanced adhesion, further supporting the limiting factor of the enzyme. These data indicate that: a)Dependence on ecto-sulfhydryls for integrin-mediated adhesion is not exclusive to the platelet; b)PDI is involved in integrin-mediated adhesion, catalyzing disulfide bond exchange; c)PDI enhances cell adhesion by both its oxidoreductase activity and as a chaperone.

Original languageEnglish
Pages (from-to)77-85
Number of pages9
JournalExperimental Cell Research
Volume381
Issue number1
DOIs
StatePublished - 1 Aug 2019

Funding

FundersFunder number
Department of Biochemistry
Goldschleger Eye Research Institute
Sackler Faculty of Medicine, Tel Aviv University
WT-PDI
Heising-Simons Foundation
University of Cambridge
Ministry of Health, State of Israel

    Keywords

    • Cell adhesion
    • Collagen
    • Disulfide exchange
    • Fibronectin
    • Integrin
    • PDI

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