Molecular Evaluation of Endoplasmic Reticulum Homeostasis Meets Humoral Immunity.

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 essay, 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.

大约三分之一的人类蛋白质组（包括膜受体和分泌蛋白）的生物合成发生在内质网（ER）中。扰乱内质网稳态的条件会激活未折叠蛋白反应（UPR）。一种“乐观的”UPR输出旨在通过加强确保内质网中蛋白质生物合成效率和保真度的机制来恢复稳态。然而，一旦UPR“认为”内质网稳态的重新调整失败，它就会转变为一种“悲观的”输出，这取决于细胞类型，将导致细胞凋亡。在本文中，我们讨论了关于UPR如何“评估”内质网应激、UPR如何被重新利用（特别是在B细胞中）以及UPR驱动的对经历稳态失败的细胞的反向选择如何服务于机体稳态和体液免疫的新兴概念。