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J. Biol. Chem., Vol. 278, Issue 40, 38935-38941, October 3, 2003

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Acid-induced Conformational Changes in Phosphoglucose Isomerase Result in Its Increased Cell Surface Association and Deposition on Fibronectin Fibrils^*

Mohammad Amraei, Zongjian Jia, Pascal Reboul  and Ivan R. Nabi 

From the Département de pathologie et biologie cellulaire, Université de Montréal, Montréal, Québec H3C 3J7, Canada and the Osteoarthritis Research Unit, Hôpital Notre-Dame, Centre Hospitalier de l'Université de Montréal, Montréal, Québec H2L 4M1, Canada

Phosphoglucose isomerase (PGI) is a glycolytic enzyme that exhibits extracellular cytokine activity as autocrine motility factor, neuroleukin, and maturation factor and that has been recently implicated as an autoantigen in rheumatoid arthritis. In contrast to its receptor-mediated endocytosis at neutral pH, addition of 25 µg/ml of either Alexa 568- or FITC-conjugated PGI to NIH-3T3 cells at progressively acid pH results in its quantitatively increased association with cell surface fibrillar structures that is particularly evident at pH 5. A similar pH-dependent cell surface association of PGI is observed for first passage human chondrocytes obtained from osteoarthritic joints. At acid pH, PGI colocalizes with fibronectin fibrils, and this association occurs directly upon addition of PGI to the cells. In contrast to the receptor-mediated endocytosis of PGI, fibril association of 25 µg/ml PGI at pH 5 is not competed with an excess (2 mg/ml) of unlabeled PGI. PGI binding at acid pH is therefore neither saturable nor mediated by its receptor. PGI is enzymatically active as a dimer and we show here by non-denaturing gel electrophoresis as well as by glutaraldehyde cross-linking that it exists at neutral pH in a tetrameric form. Increasingly acid pH results in the appearance of PGI monomers that correlates directly with its enhanced cell surface association. However, glutaraldehyde cross-linked PGI is endocytosed at neutral pH and still exhibits enhanced cell surface binding at pH 5. Circular dichroism analysis revealed pH-dependent changes in the near but not the far UV spectra indicating that the tertiary structure of the protein is specifically altered at pH 5. Conformational changes of PGI and exposure of the monomer-monomer interface under acidic conditions, such as those encountered in the synovial fluid of arthritic joints, could therefore result in its deposition on the surface of joints and the induction of an autoimmune response.

Received for publication, May 7, 2003 , and in revised form, July 21, 2003.

^* This study was supported by a grant from the Canadian Institutes of Health Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

An Investigator of the Canadian Institutes of Health Research. To whom correspondence should be addressed: Département de pathologie et biologie cellulaire, Université de Montréal, C. P. 6128, succursale A, Montréal, Québec H3C 3J7, Canada. Tel.: 514-343-6291; Fax: 514-343-2459; E-mail: ivan.robert.nabi{at}umontreal.ca.

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				A. Lagana, J. G. Goetz, N. Y, Y. Altschuler, and I. R. Nabi pH-specific sequestration of phosphoglucose isomerase/autocrine motility factor by fibronectin and heparan sulphate J. Cell Sci., September 15, 2005; 118(18): 4175 - 4185. [Abstract] [Full Text] [PDF]