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.
Highlights
Plasma cells (PCs) are the terminal effector cells of B lymphocytes, able to secrete copious amounts of antibodies [i.e., immunoglobulin (Ig) molecules], and constituting the humoral arm of adaptive immunity
To determine whether the difference in the life span between short-lived PCs and long-lived PCs correlates to the folding capacity and unfolded protein response (UPR) status of the endoplasmic reticulum (ER), we sorted splenic PCs (B220loCD138+) from K/BxN and K/BxNsf mice and compared the expression of genes encoding molecules involved in the X-box binding protein 1 (XBP1) branch of the UPR
We have described here a novel function of FK506-binding protein 13 (FKBP13) in PCs that is distinct from their PPIase and immunophilin activities
Summary
Plasma cells (PCs) are the terminal effector cells of B lymphocytes, able to secrete copious amounts of antibodies [i.e., immunoglobulin (Ig) molecules], and constituting the humoral arm of adaptive immunity. When PCs reside in milieu providing survival niches for them, such as bone marrow (BM) and inflamed sites, they terminally differentiate into post-mitotic PCs attaining a life span of months or even decades [1]. These long-lived PCs have been known to be crucial for long-lasting immunity in experimental animals and humans [2,3,4,5,6], but little is known about how they sustain viability for such a long period. The mechanism underlying how long-lived PCs evade ER stress-associated apoptosis remains largely unknown
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