Eukaryotic cells are able to discriminate between native and non‐native polypeptides, selectively transporting the former to their final destinations. Secretory proteins are scrutinized at the endoplasmic reticulum (ER)–Golgi interface. Recent findings reveal novel features of the underlying molecular mechanisms, with several chaperone networks cooperating in assisting the maturation of complex proteins and being selectively induced to match changing synthetic demands. ‘Public’ and ‘private’ chaperones, some of which enriched in specializes subregions, operate for most or selected substrates, respectively. Moreover, sequential checkpoints are distributed along the early secretory pathway, allowing efficiency and fidelity in protein secretion.

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EMBO Press is an editorially independent publishing platform for the development of EMBO scientific publications.

Aims: The endoplasmic reticulum (ER) is involved in many functions, including protein folding, redox homeostasis, and Ca ²⁺ storage and signaling. To perform these multiple tasks, the ER is composed of distinct, specialized subregions, amongst which mitochondrial-associated ER membranes (MAM) emerge as key signaling hubs. How these multiple functions are integrated with one another in living cells remains unclear. Results: Here we show that Ero1α, a key controller of oxidative folding and ER redox homeostasis, is enriched in MAM and regulates Ca ²⁺ fluxes. Downregulation of Ero1α by RNA interference inhibits mitochondrial Ca ²⁺ fluxes and modifies the activity of mitochondrial Ca ²⁺ uniporters. The overexpression of redox active Ero1α increases passive Ca ²⁺ efflux from the ER, lowering [Ca ²⁺ ] _ER and mitochondrial Ca ²⁺ fluxes in response to IP3 agonists. Innovation: The unexpected observation that Ca ²⁺ fluxes are affected by either increasing or decreasing the levels of Ero1α reveals a pivotal role for this oxidase in the early secretory compartment and implies a strict control of its amounts. Conclusions: Taken together, our results indicate that the levels, subcellular localization, and activity of Ero1α coordinately regulate Ca ²⁺ and redox homeostasis and signaling in the early secretory compartment. Antioxid. Redox Signal. 16, 1077–1087.

The biogenesis of secretory IgM occurs stepwise under stringent quality control, formation of μ2L2 preceding polymerization. How is efficiency of IgM secretion coupled to fidelity? We show here that ERp44, a soluble protein involved in thiol‐mediated retention, interacts with ERGIC‐53. Binding to this hexameric lectin contributes to ERp44 localization in the ER‐golgi intermediate compartment. ERp44 and ERGIC‐53 increase during B‐lymphocyte differentiation, concomitantly with the onset of IgM polymerization. Both preferentially bind μ2L2 and higher order intermediates. Their overexpression or silencing in non‐lymphoid cells promotes or decreases secretion of IgM polymers, respectively. In IgM‐secreting B‐lymphoma cells, μ chains interact first with BiP and later with ERp44 and ERGIC‐53. Our findings suggest that ERGIC‐53 provides a platform that receives μ2L2 subunits from the BiP‐dependent checkpoint, assisting polymerization. In this process, ERp44 couples thiol‐dependent assembly and quality control.

Glutathione peroxidases (GPXs) are enzymes that are present in almost all organisms with the primary function of limiting peroxide accumulation. In mammals, two of the eight members (GPX7 and GPX8) reside in the endoplasmic reticulum (ER). A peculiar feature of GPX8 is the concomitant presence of a conserved N-terminal transmembrane domain (TMD) and a C-terminal KDEL-like motif for ER localization. Aims: Investigating whether and how GPX8 impacts Ca ²⁺ homeostasis and signaling. Results: We show that GPX8 is enriched in mitochondria-associated membranes and regulates Ca ²⁺ storage and fluxes. Its levels correlate with [Ca ²⁺ ] _ER , and cytosolic and mitochondrial Ca ²⁺ fluxes. GPX7, which lacks a TMD, does not share these properties. Deleting or replacing the GPX8 TMD with an unrelated N-terminal membrane integration sequence abolishes all effects on Ca ²⁺ fluxes, whereas appending the GPX8 TMD to GPX7 transfers the Ca ²⁺ -regulating properties. Innovation and Conclusion: The notion that the TMD of GPX8, in addition to its enzymatic activity, is essential for regulating Ca ²⁺ dynamics reveals a novel level of integration between redox-related proteins and Ca ²⁺ signaling/homeostasis. Antioxid. Redox Signal. 27, 583–595.