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

Abstract : Phosphoglucose isomerase (PGI) is a glycolytic enzyme that exhibits extracellular cytokine activity as au-tocrine motility factor, neuroleukin, and maturation factor and that has been recently implicated as an au-toantigen in rheumatoid arthritis. In contrast to its receptor mediated endocytosis at neutral pH, addition of 25 g/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 colo-calizes 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 g/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 electrophore-sis 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 en-docytosed 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. Conforma-tional 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.
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Submitted on : Thursday, February 15, 2018 - 3:57:01 PM
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Mohammad Amraei, Zongjian Jia, Pascal Reboul, Ivan Nabi. Acid-induced Conformational Changes in Phosphoglucose Isomerase Result in Its Increased Cell Surface Association and Deposition on Fibronectin Fibrils. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2003, 278 (40), pp.38935 - 38941. ⟨10.1074/jbc.M304778200⟩. ⟨hal-01705860⟩

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