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Secreted cyclophilin A, a peptidylprolyl cis-trans isomerase, mediates matrix assembly of hensin, a protein implicated in epithelial differentiation.

ABSTRACT: Hensin is a rabbit ortholog of DMBT1, a multifunctional, multidomain protein implicated in the regulation of epithelial differentiation, innate immunity, and tumorigenesis. Hensin in the extracellular matrix (ECM) induced morphological changes characteristic of terminal differentiation in a clonal cell line (clone C) of rabbit kidney intercalated cells. Although hensin is secreted in monomeric and various oligomeric forms, only the polymerized ECM form is able to induce these phenotypic changes. Here we report that hensin secretion and matrix assembly were inhibited by the peptidylprolyl cis-trans isomerase (PPIase) inhibitors cyclosporin A (CsA) and a derivative of cyclosporin A with modifications in the d-Ser side chain (Cs9) but not by the calcineurin pathway inhibitor FK506. PPIase inhibition led to failure of hensin polymerization in the medium and ECM, plus the loss of apical cytoskeleton, apical microvilli, and the columnar epithelial shape of clone C cells. Cyclophilin A was produced and secreted into the media to a much greater extent than cyclophilins B and C. Our results also identified the direct CsA-sensitive interaction of cyclophilin A with hensin, suggesting that cyclophilin A is the PPIase that mediates the polymerization and matrix assembly of hensin. These results are significant because this is the first time a direct role of peptidylprolyl cis-trans isomerase activity has been implicated in the process of epithelial differentiation.

SUBMITTER: Peng H

PROVIDER: S-EPMC2649100 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Secreted cyclophilin A, a peptidylprolyl cis-trans isomerase, mediates matrix assembly of hensin, a protein implicated in epithelial differentiation.

Peng Hu H Vijayakumar Soundarapandian S Schiene-Fischer Cordelia C Li Hui H Purkerson Jeffrey M JM Malesevic Miroslav M Liebscher Jürgen J Al-Awqati Qais Q Schwartz George J GJ

The Journal of biological chemistry 20081226 10

Hensin is a rabbit ortholog of DMBT1, a multifunctional, multidomain protein implicated in the regulation of epithelial differentiation, innate immunity, and tumorigenesis. Hensin in the extracellular matrix (ECM) induced morphological changes characteristic of terminal differentiation in a clonal cell line (clone C) of rabbit kidney intercalated cells. Although hensin is secreted in monomeric and various oligomeric forms, only the polymerized ECM form is able to induce these phenotypic changes. ...[more]

PMID: 19112104

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Project description:The recently discovered macrolide FK506 has been demonstrated to have potent immunosuppressive activity at concentrations 100-fold lower than cyclosporin A, a cyclic undecapeptide that is used to prevent rejection after transplantation of bone marrow and organs, such as kidney, heart, and liver. After the recent discovery that the cyclosporin A-binding protein cyclophilin is identical to peptidylprolyl cis-trans isomerase, a cellular binding protein for FK506 was found to be distinct from cyclophilin but to have the same enzymatic activity. In this study, we isolated a cDNA coding for FK506-binding protein (FKBP) from human peripheral blood T cells by using mixed 20-mer oligonucleotide probes synthesized on the basis of the sequence, Glu-Asp-Gly-Lys-Lys-Phe-Asp, reported for bovine FKBP. The DNA isolated contained an open reading frame encoding 108 amino acid residues. The first 40 residues of the deduced amino acid sequence were identical to those of the reported amino-terminal sequence of bovine FKBP, indicating that the DNA sequence isolated represents the gene coding for FKBP. Computer-assisted analysis of the deduced amino acid sequence indicates that FKBP exhibits no internal homology and does not have significant sequence similarity to any other amino acid sequences of known proteins, including cyclophilin. This result suggests that two catalytically similar proteins, cyclophilin and FKBP, evolved independently. In Northern blot analysis, mRNA species of approximately 1.8 kilobases that hybridized with human FKBP cDNA were detected in poly(A)+ RNAs from brain, lung, liver, and placental cells and leukocytes. Induction of Jurkat leukemic T cells with phorbol 12-myristate 13-acetate and ionomycin did not affect the level of FKBP mRNA. Southern blot analysis of human genomic DNA digested with different restriction enzymes suggests the existence of only a few copies of the DNA sequence encoding FKBP. This is in contrast to the result that as many as 20 copies of the cyclophilin gene and possible pseudogenes may be present in the mammalian genome.

Dataset Information

Secreted cyclophilin A, a peptidylprolyl cis-trans isomerase, mediates matrix assembly of hensin, a protein implicated in epithelial differentiation.

Publications

Secreted cyclophilin A, a peptidylprolyl cis-trans isomerase, mediates matrix assembly of hensin, a protein implicated in epithelial differentiation.

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