Ufbp1 promotes plasma cell development and ER expansion by modulating distinct branches of UPR

Abstract

The IRE1α/XBP1 branch of unfolded protein response (UPR) pathway has a critical function in endoplasmic reticulum (ER) expansion in plasma cells via unknown mechanisms; interestingly, another UPR branch, PERK, is suppressed during plasma cell development. Here we show that Ufbp1, a target and cofactor of the ufmylation pathway, promotes plasma cell development by suppressing the activation of PERK. By contrast, the IRE1α/XBP1 axis upregulates the expression of Ufbp1 and ufmylation pathway genes in plasma cells, while Ufbp1 deficiency impairs ER expansion in plasma cells and retards immunoglobulin production. Structure and function analysis suggests that lysine 267 of Ufbp1, the main lysine in Ufbp1 that undergoes ufmylation, is dispensable for the development of plasmablasts, but is required for immunoglobulin production and stimulation of ER expansion in IRE1α-deficient plasmablasts. Thus, Ufbp1 distinctly regulates different branches of UPR pathway to promote plasma cell development and function.

PDGFA-associated protein 1 protects mature B lymphocytes from stress-induced cell death and promotes antibody gene diversification

“…S5 B). In agreement with a previous report (Zhu et al, 2019), Atf4 was markedly expressed only at late time points after activation in control splenocytes (Fig. 5 D).…”

“…In contrast, the Perk arm of the UPR is dispensable for plasma cell development (Zhang et al, 2005;Gass et al, 2008). Furthermore, this pathway is suppressed during differentiation of naïve B cells into plasma cells (Ma et al, 2010;Gass et al, 2008;Zhang et al, 2005), and unrestricted Perk-eIF2α-Atf4 signaling in activated B cells blocks the formation of plasma cells (Zhu et al, 2019). Given the up-regulated expression of Atf4 in Pdap1-deficient B cells, we considered the possibility that plasma cell development might be impaired in the absence of Pdap1.…”

Pdap1 protects mature B lymphocytes from stress-induced cell death and promotes antibody gene diversification

“…In line with this point, although mature B cells retain the potential to activate all three arms of the UPR in response to pharmacological triggers of the pathway, the Perk branch is suppressed during normal differentiation of activated B cells into plasma cells (Ma et al, 2010;Gass et al, 2008;Zhang et al, 2005). It is interesting to notice that non-physiological Perk-eIF2a-Atf4 signaling after B cell activation blocks the formation of plasma cells (Zhu et al, 2019). In Pdap1 F/F Cd19 Cre/+ splenocytes, the Perk-eIF2a-Atf4 pathway is already active under resting conditions, and the increased loss of mitochondrial membrane potential and apoptosis were observed at early, but not late, stages after activation.…”

“…The eIF2a-Atf4 pathway is normally suppressed in splenic B cells, and is induced only at later time points after activation, when splenocyte cultures exhibit a general fitness decline ( Fig. 4D, control cells, and (Zhu et al, 2019)). In contrast to control cells, resting B cells from Pdap1 F/F Cd19 Cre/+ spleens displayed a marked phosphorylation of eIF2a and detectable levels of Atf4 protein, thus indicating a baseline activation of the ISR ( Fig 4D).…”

“…In contrast, the Perk arm of the UPR is dispensable for plasma cell development (Zhang et al, 2005;Gass et al, 2008). Furthermore, this pathway is suppressed during differentiation of naïve B cells into plasma cells (Ma et al, 2010;Gass et al, 2008;Zhang et al, 2005), and unrestricted Perk-eIF2a-Atf4 signaling in activated B cells blocks the formation of plasma cells (Zhu et al, 2019). Given the upregulated expression of Atf4 in Pdap1deficient B cells, we considered the possibility that plasma cell development might be impaired in the absence of Pdap1.…”