title: FKBP65-dependent peptidyl-prolyl isomerase activity potentiates the lysyl hydroxylase 2-driven collagen cross-link switch.
abstract: Bruck Syndrome is a connective tissue disease associated with inactivating mutations in lysyl hydroxylase 2 (LH2/PLOD2) or FK506 binding protein 65 (FKBP65/FKBP10). However, the functional relationship between LH2 and FKBP65 remains unclear. Here, we postulated that peptidyl prolyl isomerase (PPIase) activity of FKBP65 positively modulates LH2 enzymatic activity and is critical for the formation of hydroxylysine-aldehyde derived intermolecular collagen cross-links (HLCCs). To test this hypothesis, we analyzed collagen cross-links in Fkbp10-null and -wild-type murine embryonic fibroblasts. Although LH2 protein levels did not change, FKBP65 deficiency significantly diminished HLCCs and increased the non-hydroxylated lysine-aldehyde-derived collagen cross-links (LCCs), a pattern consistent with loss of LH2 enzymatic activity. The HLCC-to-LCC ratio was rescued in FKBP65-deficient murine embryonic fibroblasts by reconstitution with wild-type but not mutant FKBP65 that lacks intact PPIase domains. Findings from co-immunoprecipitation, protein-fragment complementation, and co-immunofluorescence assays showed that LH2 and FKBP65 are part of a common protein complex. We conclude that FKBP65 regulates LH2-mediated collagen cross-linking. Because LH2 promotes fibrosis and cancer metastasis, our findings suggest that pharmacologic strategies to target FKBP65 and LH2 may have complementary therapeutic activities.
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX-77030, USA.
authors.forename: Yulong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Oral and Craniofacial Health Sciences, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC-27599, USA.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Terajima
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX-77030, USA.
authors.forename: Priyam
authors.initials: P
authors.lastname: Banerjee
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX-77030, USA.
authors.forename: Houfu
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX-77030, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX-77030, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Yu
authors.affiliation: Oral and Craniofacial Health Sciences, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC-27599, USA.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Yamauchi
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX-77030, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Kurie
mesh_terms: D000818:Animals; D003094:Collagen / Q000378:metabolism*; D003432:Cross-Linking Reagents / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D051379:Mice; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D000072417:Protein Domains; D022021:Tacrolimus Binding Proteins / Q000378:metabolism*
chemical_list: D003432:Cross-Linking Reagents; D003094:Collagen; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; D022021:Tacrolimus Binding Proteins; D019696:Peptidylprolyl Isomerase