In the ER, proteins undergo quality control, which ensures that only correctly folded proteins exit the ER. Misfolded proteins are extracted from the ER for endoplasmic reticulum-associated degradation (ERAD) (Fig. 1). ERAD occurs in three major steps: (1) detection by the ER quality control machinery and targeting for ERAD, (2) transport across the ER membrane into the cytosol, and (3) ubiquitylation and degradation by the proteasome.

Fig1. PROTEIN DEGRADATION PATHWAYS AND UNFOLDED PROTEIN RESPONSE. The major pathway of selective protein degradation in eukaryotic cells uses ubiquitin as a marker that targets proteins for rapid proteolysis thanks to the proteasome complex. This pathway deals also with misfolded proteins that could accumulate in the endoplasmic reticulum (ER) during stress or disease. Misfolded proteins are extracted from the ER for endoplasmic reticulum-associated degradation (ERAD). Proteasome inhibitors are the therapeutic backbone for the treatment of several hematologic diseases, such as multiple myeloma (MM).

The ER monitors the amount of unfolded protein in its lumen. When that number exceeds a certain threshold, ER sensors activate the so-called unfolded protein response (UPR). A number of cellular insults can disrupt protein folding and cause accumulation of unfolded proteins in the ER lumen. The UPR is an adaptive response signaled through three ER-localized transmembrane proteins PERK, IRE1, and ATF6. These proteins function as sensors through the properties of their ER-luminal domains and trigger a concerted response through the function of their cytosolic domains aimed to (i) limit accumulation of unfolded protein through reduction of pro tein synthesis, to (ii) increase the degradation of unfolded protein, and to (iii) increase the ER protein-folding capacity. PERK-mediated phosphorylation of eIF2α attenuates general mRNA translation while increasing translation of the transcription factor ATF4 that induces transcription of UPR genes. IRE1 carries protein kinase and endoribonuclease activities that, upon activation, mediate unconventional splicing of a 26-base intron from the basic leucine zipper (bZip) transcription factor XBP1 mRNA. ATF6 is transported to the Golgi compartment upon accumulation of unfolded protein in the ER lumen, where it is cleaved by two proteases to release its cytosolic fragment also containing a bZip-transcription factor. Both XBP1 and ATF6 upregulate transcription of ER “stress elements” to correct protein folding. If the UPR adaptive response is not sufficient to correct the protein folding defect, the cells enter apoptotic death. The ER in this role is regarded as a sensor of perturbations of cell homeostasis and both activation and defects of the UPR are central to many dis ease processes, ranging from metabolic, neurologic, and infectious diseases to cancer.75 In hematologic malignancies, such as multiple myeloma, the UPR response mediated by the IRE1 axis is highly activated and essential for cell survival. The role of the UPR in cancer survival and cancer immunogenicity is reviewed in Vanacker et al.[1]

References

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[1] Vanacker H, Vetters J, Moudombi L, et al. Emerging role of the unfolded protein response in tumor immunosurveillance. Trends Cancer. 2017;3(7):491–505.

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مواضيع ذات صلة

How AraC Protein Loops and Unloops

DNA Looping and Repression of araBAD

Binding Sites of the ara Regulatory Proteins

Protein Folding and Modifications in the Endoplasmic Reticulum

Protein Modifications

Regulating AraC Synthesis

Repression by AraC

Detection and Isolation of AraC Protein

Genetics of the Arabinose System

The Eukaryotic Genome

Nucleic Acids and Their Organization in Eukaryotic, Prokaryotic, and Viral Genomes

The Sugar Arabinose and Arabinose Metabolism