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

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.

Machine learning-based prediction of candidate gene biomarkers correlated with immune infiltration in patients with idiopathic pulmonary fibrosis

“…Some results of this study are consistent with those of previous studies. The expression of FK506-binding protein (FKBP) prolyl isomerase 11 (FKBP11) is elevated in the lung tissues of patients with IPF, and FKBP11 specifically localises to antibody-producing plasma cells ( 64 ). In a study, compared with control mice, bleomycin-treated mice had an increased proportion of pulmonary IgA(+) germinal centres and plasma cells, and autoreactive IgA was identified as a diagnostic biomarker for IPF ( 65 ).…”

Effects of immunophilin inhibitors and non-immunosuppressive analogs on coronavirus replication in human infection models

“…Why FK506 displayed cell type-specific effects on coronavirus replication in our study remains unclear. The 15 human FKBPs that have so far been identified are characterized by divergent functions, cell type-specific expression, and highly variable binding affinities to FK506 ( Lammers et al., 2010 ; Staab-Weijnitz et al., 2015 ; Tong and Jiang, 2015 ; Preisendorfer et al., 2022 ). To date, it has not been elucidated which FKBP is responsible for the anti-coronaviral effect of FK506, and it is more than likely that FKBP expression differs considerably in the three cell types used.…”

“…They are also involved in protein folding as molecular chaperones and play a role in receptor signaling and protein trafficking. They are often cell type-specifically expressed and act on specific folding substrates ( Lammers et al., 2010 ; Staab-Weijnitz et al., 2015 ; Preisendorfer et al., 2022 ).…”

State of the Art in Idiopathic Pulmonary Fibrosis

“…The cellular heterogeneity of IPF is further discussed by Preisendörfer et al, who stress the potential role of B cells in IPF pathobiology [ 16 ]. The pathological relevance of B-cell accumulation in the lungs of IPF patients is supported by the presence of circulating autoantibodies and the increased concentration of B-lymphocyte stimulator factor (BLyS) in IPF plasma.…”

“…The latter may lead to higher susceptibility of A549 cells to ER stress-induced cell death. Although the authors failed to demonstrate the importance of FKBP11 for antibody production in the loss-of-function approaches, these results provide further evidence for the role of auto-immunogenicity in IPF pathogenesis [ 16 ].…”