FK506-Binding Protein 2 Participates in Proinsulin Folding
Carolin Hoefner,
Tenna Holgersen Bryde,
Celina Pihl,
Sylvia Naiga Tiedemann,
Sophie Emilie Bresson,
Hajira Ahmed Hotiana,
Muhammad Saad Khilji,
Theodore Dos Santos,
Michele Puglia,
Paola Pisano,
Mariola Majewska,
Julia Durzynska,
Kristian Klindt,
Justyna Klusek,
Marcelo J. Perone,
Robert Bucki,
Per Mårten Hägglund,
Pontus Emanuel Gourdon,
Kamil Gotfryd,
Edyta Urbaniak,
Malgorzata Borowiak,
Michael Wierer,
Patrick Edward MacDonald,
Thomas Mandrup-Poulsen,
Michal Tomasz Marzec
Affiliations
Carolin Hoefner
Inflammation, Metabolism and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Tenna Holgersen Bryde
Inflammation, Metabolism and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Celina Pihl
Inflammation, Metabolism and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Sylvia Naiga Tiedemann
Inflammation, Metabolism and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Sophie Emilie Bresson
Inflammation, Metabolism and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Hajira Ahmed Hotiana
Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Muhammad Saad Khilji
Inflammation, Metabolism and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Theodore Dos Santos
Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada
Michele Puglia
Proteomics Research Infrastructure, University of Copenhagen, 2200 Copenhagen, Denmark
Paola Pisano
Proteomics Research Infrastructure, University of Copenhagen, 2200 Copenhagen, Denmark
Mariola Majewska
Department of Genetics, Institute of Experimental Biology, Faculty of Biology, Adam Mickiewicz University, 61-712 Poznań, Poland
Julia Durzynska
Department of Genetics, Institute of Experimental Biology, Faculty of Biology, Adam Mickiewicz University, 61-712 Poznań, Poland
Kristian Klindt
Inflammation, Metabolism and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Justyna Klusek
Laboratory of Medical Genetics, Department of Surgical Medicine, Collegium Medicum, Jan Kochanowski University, 25-406 Kielce, Poland
Marcelo J. Perone
Immuno-Endocrinology, Diabetes & Metabolism Laboratory, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, CONICET-Universidad Austral, Buenos Aires B1629AHJ, Argentina
Robert Bucki
Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of Białystok, 15-089 Białystok, Poland
Per Mårten Hägglund
Inflammation, Metabolism and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Pontus Emanuel Gourdon
Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Kamil Gotfryd
Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Edyta Urbaniak
Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, 61-712 Poznań, Poland
Malgorzata Borowiak
Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, 61-712 Poznań, Poland
Michael Wierer
Proteomics Research Infrastructure, University of Copenhagen, 2200 Copenhagen, Denmark
Patrick Edward MacDonald
Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada
Thomas Mandrup-Poulsen
Inflammation, Metabolism and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Michal Tomasz Marzec
Inflammation, Metabolism and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Apart from chaperoning, disulfide bond formation, and downstream processing, the molecular sequence of proinsulin folding is not completely understood. Proinsulin requires proline isomerization for correct folding. Since FK506-binding protein 2 (FKBP2) is an ER-resident proline isomerase, we hypothesized that FKBP2 contributes to proinsulin folding. We found that FKBP2 co-immunoprecipitated with proinsulin and its chaperone GRP94 and that inhibition of FKBP2 expression increased proinsulin turnover with reduced intracellular proinsulin and insulin levels. This phenotype was accompanied by an increased proinsulin secretion and the formation of proinsulin high-molecular-weight complexes, a sign of proinsulin misfolding. FKBP2 knockout in pancreatic β-cells increased apoptosis without detectable up-regulation of ER stress response genes. Interestingly, FKBP2 mRNA was overexpressed in β-cells from pancreatic islets of T2D patients. Based on molecular modeling and an in vitro enzymatic assay, we suggest that proline at position 28 of the proinsulin B-chain (P28) is the substrate of FKBP2’s isomerization activity. We propose that this isomerization step catalyzed by FKBP2 is an essential sequence required for correct proinsulin folding.
