The Function of FK506-Binding Protein 13 in Protein Quality Control Protects Plasma Cells from Endoplasmic Reticulum Stress-Associated Apoptosis

Abstract

Plasma cells (PCs) are exposed to intense endoplasmic reticulum (ER) stress imposed by enormous rates of immunoglobulin (Ig) synthesis and secretion. Therefore, protein homeostasis is crucial for the survival of PCs, but its molecular mechanism remains largely unknown. Here, we found marked overexpression of FK506-binding protein 13 (FKBP13) in long-lived PCs from autoimmune mice and investigated its function using a plasmacytoma cell line secreting IgA. FKBP13 expression was induced largely in the lumen of ER in response to treatment with an ER stressor tunicamycin or overexpression of an adaptive unfolded protein response (UPR) protein X-box binding protein 1 (XBP1). Silencing of FKBP13 expression led to induction of molecules involved in the terminal UPR and ER stress-associated apoptosis. FKBP13 interacted with Ig, facilitated its ubiquitination, and lowered the extent of ER stress. FKBP13 overexpression caused a significant reduction in secreted IgA in plasmacytoma cells, and FKBP13 knockdown exerted an opposite effect. Rapamycin interfered with the interaction between FKBP13 and IgA and enhanced the amount of secreted IgA. Importantly, the level of FKBP13 was inversely correlated with the amount of secreted antibody in long-lived PCs from autoimmune mice. These results suggest that FKBP13 is a marker of long-lived PCs and a component of XBP1-dependent ER protein homeostasis. FKBP13 is likely to act as a molecular chaperone that delivers misfolded ER clients, including Ig, to ER-associated degradation, so reducing proteotoxic stress on the PC. Our data reveal a novel cytoprotective role for FKBP13 in long-lived PCs occurring at the expense of antibody production.

FKBP Ligands—Where We Are and Where to Go?

“…Further, FKBP13 is thought to play a role in protein folding in the ER (Walensky et al, 1998). Recently, FKBP13 was identified as a key regulator of protein homeostasis in long-lived plasma cells (Jeong et al, 2017). By interaction with immunoglobulin (Ig) the ubiquitination of Ig is facilitated, leading to lowered levels of ER stress.…”

Unravel the molecular mechanism of XBP1 in regulating the biology of cancer cells

“…However, no relationships between cytoplasmic XBP1s and survival are found 9. FK506-binding protein 13 (FKBP13), a chaperone that acts as the downstream factor of XBP1, has been demonstrated to interact with the surplus Ig molecules or mis-folded proteins to the ubiquitin-dependent degradation system in plasma cells, leading to amelioration of ER stress 10. Thus, XBP1-FKBP13 axis becomes the potential target for managing diseases.…”

No Impact of Long-Term Fingolimod Treatment on Fecal Secretory Immunoglobulin A Levels in Patients With Multiple Sclerosis

“…The sIgA response belongs to the largest humoral immune system and serves as the first line of defense in protecting the intestinal epithelium from enteric toxins and pathogenic microorganisms (Brandtzaeg, 2009;Brandtzaeg, 2013). The IgA is a polymeric immunoglobulin with a "secretory component" produced by plasmablasts in the intestinal mucosa after B cell induction in lymphoid tissue (Brandtzaeg, 2013).…”

“…The sIgA response belongs to the largest humoral immune system and serves as the first line of defense in protecting the intestinal epithelium from enteric toxins and pathogenic microorganisms (Brandtzaeg, 2009;Brandtzaeg, 2013). The IgA is a polymeric immunoglobulin with a "secretory component" produced by plasmablasts in the intestinal mucosa after B cell induction in lymphoid tissue (Brandtzaeg, 2013). Through a process known as immune exclusion, sIgA promotes the clearance of antigens and pathogenic microorganisms from the intestinal lumen by blocking their access to epithelial receptors, entrapping them in mucus and facilitating their removal by peristaltic and mucociliary activity (Brandtzaeg, 2009).…”

“…Additionally, the sIgA may have the capacity to directly regulate bacterial virulence factors accounting for protective effects against several antigens and to transport immune complexes across the intestinal epithelium to lymphoid tissues with a regulation of pro-inflammatory responses ( Mantis et al, 2002 , 2011 ; Boullier et al, 2009 ; Chairatana and Nolan, 2017 ). In addition, sIgA modulates the mucosal immunity and intestinal homeostasis through mechanisms that have only recently been revealed ( Brandtzaeg, 2013 ). The sIgA influences also the gut microbiota in a complex relationship through Fab-dependent and -independent mechanisms, an effect that is already present on neonatal exposure to commensal microorganisms ( Corthesy, 2007 ; Sekirov et al, 2010 ; Mantis et al, 2011 ; Schofield and Palm, 2018 ; Chang and Kao, 2019 ).…”