Bergmann, Timothy J. Fregno, Ilaria Fumagalli, Fiorenza Rinaldi, Andrea Bertoni, Francesco Boersema, Paul J. Picotti, Paola Molinari, Maurizio 2018-02-16 The stress sensors ATF6, IRE1, and PERK monitor deviations from homeostatic conditions in the endoplasmic reticulum (ER), a protein biogenesis compartment of eukaryotic cells. Their activation elicits unfolded protein responses (UPR) to reestablish proteostasis. UPR have been extensively investigated in cells exposed to chemicals that activate ER stress sensors by perturbing calcium, N-glycans, or redox homeostasis. Cell responses to variations in luminal load with unfolded proteins are, in contrast, poorly characterized. Here, we compared gene and protein expression profiles in HEK293 cells challenged with ER stress–inducing drugs or expressing model polypeptides. Drug titration to limit up-regulation of the endogenous ER stress reporters heat shock protein family A (Hsp70) member 5 (BiP/HSPA5) and homocysteine-inducible ER protein with ubiquitin-like domain 1 (HERP/HERPUD1) to levels comparable with luminal accumulation of unfolded proteins substantially reduced the amplitude of both transcriptional and translational responses. However, these drug-induced changes remained pleiotropic and failed to recapitulate responses toERload with unfolded proteins. These required unfolded protein association with BiP andinduced amuchsmaller subset of genes participating in a chaperone complex that binds unfolded peptide chains. In conclusion, UPR resulting from ER load with unfolded proteins proceed via a well-defined and fine-tuned pathway, whereas even mild chemical stresses caused by compounds often used to stimulate UPR induce cellular responses largely unrelated to the UPR or ER-mediated protein secretion. application/pdf https://localhost:5000/ark:/12658/srd1318888 https://susi.usi.ch/global/documents/318888 https://susi.usi.ch/documents/318888/files/1571_Bergmann_JBC_UPR.pdf eng info:eu-repo/semantics/altIdentifier/doi/10.1074/jbc.RA117.001484 info:eu-repo/semantics/altIdentifier/ark/12658/srd1318888 info:eu-repo/semantics/openAccess CC BY Journal of biological chemistry. - 2018, vol. 293, no. 15, p. 5600-5612 ER quality control Endoplasmic reticulum stress (ER stress) Molecular chaperone Protein folding Protein misfolding Unfolded protein response (UPR) info:eu-repo/classification/udc/61 Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides http://purl.org/coar/resource_type/c_6501