Molecular Evaluation of Endoplasmic Reticulum Homeostasis Meets Humoral Immunity

• Published in: Trends in cell biology 2021-07, Vol.31 (7), p.529-541
• Main Authors: van Anken, Eelco, Bakunts, Anush, Hu, Chih-Chi Andrew, Janssens, Sophie, Sitia, Roberto
• Format: Article
• Language: English
• Subjects: antibody production; Apoptosis; B cell development; Biosynthesis; Endoplasmic reticulum; Homeostasis; Humoral immunity; Immunity; Lymphocytes B; Protein folding; Proteins; Proteomes; proteostasis; RIDD; unfolded protein response
• ISSN: 0962-8924; 1879-3088
• DOI: 10.1016/j.tcb.2021.02.004

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 XBP1U 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.