2. Academic Validation
  3. FK506-Binding Protein 11 Is a Novel Plasma Cell-Specific Antibody Folding Catalyst with Increased Expression in Idiopathic Pulmonary Fibrosis

FK506-Binding Protein 11 Is a Novel Plasma Cell-Specific Antibody Folding Catalyst with Increased Expression in Idiopathic Pulmonary Fibrosis

  • Cells. 2022 Apr 14;11(8):1341. doi: 10.3390/cells11081341.
Stefan Preisendörfer 1,  Yoshihiro Ishikawa 2,  Elisabeth Hennen 1,  Stephan Winklmeier 3,  Jonas C Schupp 4 5,  Larissa Knüppel 1,  Isis E Fernandez 1 6,  Leonhard Binzenhöfer 1,  Andrew Flatley 7,  Brenda M Juan-Guardela 4,  Clemens Ruppert 8,  Andreas Guenther 8,  Marion Frankenberger 1,  Rudolf A Hatz 9 10,  Nikolaus Kneidinger 6,  Jürgen Behr 6,  Regina Feederle 7,  Aloys Schepers 7,  Anne Hilgendorff 1,  Naftali Kaminski 4,  Edgar Meinl 3,  Hans Peter Bächinger 2,  Oliver Eickelberg 1,  Claudia A Staab-Weijnitz 1
Affiliations

Affiliations

  • 1 Institute of Lung Health and Immunity and Comprehensive Pneumology Center with the CPC-M bioArchive, Member of the German Center of Lung Research (DZL), Helmholtz-Zentrum München, 81377 Munich, Germany.
  • 2 Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, OR 97239, USA.
  • 3 Institute of Clinical Neuroimmunology, Biomedical Center and LMU Klinikum, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
  • 4 Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
  • 5 Department of Respiratory Medicine, Hannover Medical School, Biomedical Research in End-Stage and Obstructive Lung Disease Hannover, Member of the German Center for Lung Research (DZL), 30625 Hannover, Germany.
  • 6 Department of Medicine V, LMU Klinikum, Ludwig-Maximilians-Universität München, Member of the German Center of Lung Research (DZL), 81377 Munich, Germany.
  • 7 Monoclonal Antibody Core Facility, Institute for Diabetes and Obesity, Helmholtz-Zentrum München, 85764 Neuherberg, Germany.
  • 8 Department of Internal Medicine, Medizinische Klinik II, Member of the German Center of Lung Research (DZL), 35392 Giessen, Germany.
  • 9 Thoraxchirurgisches Zentrum, Klinik für Allgemeine-, Viszeral-, Transplantations-, Gefäß- und Thoraxchirurgie, LMU Klinikum, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
  • 10 Asklepios Fachkliniken München-Gauting, 82131 Gauting, Germany.
PMID: 35456020 DOI: 10.3390/cells11081341
Abstract

Antibodies are central effectors of the adaptive immune response, widespread used therapeutics, but also potentially disease-causing biomolecules. Antibody folding catalysts in the plasma cell are incompletely defined. Idiopathic pulmonary fibrosis (IPF) is a fatal chronic lung disease with increasingly recognized autoimmune features. We found elevated expression of FK506-binding protein 11 (FKBP11) in IPF lungs where FKBP11 specifically localized to antibody-producing plasma cells. Suggesting a general role in plasma cells, plasma cell-specific FKBP11 expression was equally observed in lymphatic tissues, and in vitro B cell to plasma cell differentiation was accompanied by induction of FKBP11 expression. Recombinant human FKBP11 was able to refold IgG antibody in vitro and inhibited by FK506, strongly supporting a function as antibody peptidyl-prolyl cis-trans isomerase. Induction of ER stress in cell lines demonstrated induction of FKBP11 in the context of the unfolded protein response in an X-box-binding protein 1 (XBP1)-dependent manner. While deficiency of FKBP11 increased susceptibility to ER stress-mediated cell death in an alveolar epithelial cell line, FKBP11 knockdown in an antibody-producing hybridoma cell line neither induced cell death nor decreased expression or secretion of IgG antibody. Similarly, antibody secretion by the same hybridoma cell line was not affected by knockdown of the established antibody peptidyl-prolyl isomerase Cyclophilin B. The results are consistent with FKBP11 as a novel XBP1-regulated antibody peptidyl-prolyl cis-trans isomerase and indicate significant redundancy in the ER-resident folding machinery of antibody-producing hybridoma cells.

Keywords

ER stress; FK506-binding protein; antibody folding; immunophilin; interstitial lung disease; lung fibrosis; peptidyl-prolyl isomerase; tacrolimus.

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