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The biosynthesis of about one third of the human proteome, including membrane receptors and secreted proteins, occurs in the endoplasmic reticulum (ER). Conditions that perturb ER homeostasis activate the unfolded protein response (UPR). An 'optimistic' UPR output aims at restoring homeostasis by reinforcement of machineries that guarantee efficiency and fidelity of protein biogenesis in the ER. Yet, once the UPR 'deems' that ER homeostatic readjustment fails, it transitions to a 'pessimistic' output, which, depending on the cell type, will result in apoptosis. In this article, we discuss emerging concepts on how the UPR 'evaluates' ER stress, how the UPR is repurposed, in particular in B cells, and how UPR-driven counter-selection of cells undergoing homeostatic failure serves organismal homeostasis and humoral immunity. Endoplasmic reticulum (ER) stress sensing occurs in a ratiometric fashion: the ratio of binding immunoglobulin protein (BiP) levels over its clients determines the unfolded protein response (UPR) signaling amplitude. This insight unifies previous models of UPR activation. UPR-driven ER homeostatic readjustment is successful only when BiP levels rise to eclipse (again) those of its clients. Otherwise, homeostatic failure and client-driven proteotoxicity ensues. Upon ER homeostatic failure, the UPR sensor IRE1α is chronically maximally activated, such that, through splicing, it 'consumes' available stores of its main substrate XBP1 U mRNA, and as a result, commits to regulated IRE1-dependent decay (RIDD). Splicing-to-RIDD transitioning thus heralds a shift from an 'optimistic' to a 'pessimistic' UPR, which may entail apoptosis. Immunologically driven Ig sequence variability inherently leads to ER homeostatic failure in many precursor B cells. Thus, the UPR can serve to counter-select against 'faulty' B cells. [ABSTRACT FROM AUTHOR]

Plasma cells differentiate from B lymphocytes to sustain antibody production. As professional secretors, they allow dissecting proteostasis in the exocytic compartment, the stresses that protein production entails and their possible roles in signaling. Most plasma cells are short-lived to limit antibody responses. After a few days of intense immunoglobulin production, they undergo apoptosis, offering a unique model of cellular senescence. Recent observations reveal that proteotoxic stresses physiologically contribute to regulate their biogenesis, function and lifespan, explaining partly the sensitivity of multiple myeloma cells to proteasome inhibitors. This essay summarizes these plasma cell lessons, and their general implications for the regulation of proteostasis, cell senescence and cancer therapeutics. [Copyright &y& Elsevier]

• High Ca2+ turnover is distinctive for the Ca2+ homeostasis in secretory cells. • The Ca2+ leak from ER is enhanced in secretory cells. • High expression of Sec61 translocons enhances the Ca2+ leak from ER. • Massive Ca2+ entry backs up the large Sec61-mediated Ca2+ leak in secretory cells. The endoplasmic reticulum (ER) is extensively remodelled during the development of professional secretory cells to cope with high protein production. Since ER is the principal Ca2+ store in the cell, we characterised the Ca2+ homeostasis in NALM-6 and RPMI 8226 cells, which are commonly used as human pre-B and antibody secreting plasma cell models, respectively. Expression levels of Sec61 translocons and the corresponding Sec61-mediated Ca2+ leak from ER, Ca2+ storage capacity and store-operated Ca2+ entry were significantly enlarged in the secretory RPMI 8226 cell line. Using an immunoglobulin M heavy chain producing HeLa cell model, we found that the enlarged Ca2+ storage capacity and Ca2+ leak from ER are linked to ER expansion. Our data delineates a developmental remodelling of Ca2+ homeostasis in professional secretory cells in which a high Sec61-mediated Ca2+ leak and, thus, a high Ca2+ turnover in the ER is backed up by enhanced store-operated Ca2+ entry. [Display omitted] [ABSTRACT FROM AUTHOR]

The unfolded protein response (UPR) governs homeostasis of both luminal content and membrane of the endoplasmic reticulum (ER). In Molecular Cell , Halbleib et al. identified how a twist in the juxta-membrane amphipathic helix of the UPR transducer Ire1 in yeast is essential for responding to both proteostatic and lipostatic ER stress. [ABSTRACT FROM AUTHOR]