Less is Better: Various Means to Reduce Protein Load in the Endoplasmic Reticulum

Overview

Journal FEBS J

Specialty Biochemistry

Date 2024 Jun 12

PMID 38865586

Authors

Salam Dabsan

Gal Twito

Suma Biadsy

Aeid Igbaria

Affiliations

Soon will be listed here.

Abstract

The endoplasmic reticulum (ER) is an important organelle that controls the intracellular and extracellular environments. The ER is responsible for folding almost one-third of the total protein population in the eukaryotic cell. Disruption of ER-protein folding is associated with numerous human diseases, including metabolic disorders, neurodegenerative diseases, and cancer. During ER perturbations, the cells deploy various mechanisms to increase the ER-folding capacity and reduce ER-protein load by minimizing the number of substrates entering the ER to regain homeostasis. These mechanisms include signaling pathways, degradation mechanisms, and other processes that mediate the reflux of ER content to the cytosol. In this review, we will discuss the recent discoveries of five different ER quality control mechanisms, including the unfolded protein response (UPR), ER-associated-degradation (ERAD), pre-emptive quality control, ER-phagy and ER to cytosol signaling (ERCYS). We will discuss the roles of these processes in decreasing ER-protein load and inter-mechanism crosstalk.

Citing Articles

Preliminary analysis of the role of small hepatitis B surface proteins mutations in the pathogenesis of occult hepatitis B infection via the endoplasmic reticulum stress-induced UPR-ERAD pathway.

Huang C, Zhang H, Wang J, Li J, Liu Q, Zong Q Open Life Sci. 2025; 20(1):20220951.

PMID: 39926475 PMC: 11806202. DOI: 10.1515/biol-2022-0951.

References

Okamura K, Kimata Y, Higashio H, Tsuru A, Kohno K . Dissociation of Kar2p/BiP from an ER sensory molecule, Ire1p, triggers the unfolded protein response in yeast. Biochem Biophys Res Commun. 2000; 279(2):445-50. DOI: 10.1006/bbrc.2000.3987. View

Calfon M, Zeng H, Urano F, Till J, Hubbard S, Harding H . IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature. 2002; 415(6867):92-6. DOI: 10.1038/415092a. View

Reggiori F, Molinari M . ER-phagy: mechanisms, regulation, and diseases connected to the lysosomal clearance of the endoplasmic reticulum. Physiol Rev. 2022; 102(3):1393-1448. PMC: 9126229. DOI: 10.1152/physrev.00038.2021. View

Deshaies R, Sanders S, Feldheim D, Schekman R . Assembly of yeast Sec proteins involved in translocation into the endoplasmic reticulum into a membrane-bound multisubunit complex. Nature. 1991; 349(6312):806-8. DOI: 10.1038/349806a0. View

Fribley A, Evenchik B, Zeng Q, Park B, Guan J, Zhang H . Proteasome inhibitor PS-341 induces apoptosis in cisplatin-resistant squamous cell carcinoma cells by induction of Noxa. J Biol Chem. 2006; 281(42):31440-7. DOI: 10.1074/jbc.M604356200. View

Cui Y, Parashar S, Ferro-Novick S . A new role for a COPII cargo adaptor in autophagy. Autophagy. 2019; 16(2):376-378. PMC: 6984482. DOI: 10.1080/15548627.2019.1699347. View

LEVIN D, Petryshyn R, LONDON I . Characterization of double-stranded-RNA-activated kinase that phosphorylates alpha subunit of eukaryotic initiation factor 2 (eIF-2 alpha) in reticulocyte lysates. Proc Natl Acad Sci U S A. 1980; 77(2):832-6. PMC: 348375. DOI: 10.1073/pnas.77.2.832. View

Hollien J, Lin J, Li H, Stevens N, Walter P, Weissman J . Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. J Cell Biol. 2009; 186(3):323-31. PMC: 2728407. DOI: 10.1083/jcb.200903014. View

Adachi Y, Yamamoto K, Okada T, Yoshida H, Harada A, Mori K . ATF6 is a transcription factor specializing in the regulation of quality control proteins in the endoplasmic reticulum. Cell Struct Funct. 2008; 33(1):75-89. DOI: 10.1247/csf.07044. View

10.

Geiger R, Andritschke D, Friebe S, Herzog F, Luisoni S, Heger T . BAP31 and BiP are essential for dislocation of SV40 from the endoplasmic reticulum to the cytosol. Nat Cell Biol. 2011; 13(11):1305-14. DOI: 10.1038/ncb2339. View

11.

Zhang P, McGrath B, Reinert J, Olsen D, Lei L, Gill S . The GCN2 eIF2alpha kinase is required for adaptation to amino acid deprivation in mice. Mol Cell Biol. 2002; 22(19):6681-8. PMC: 134046. DOI: 10.1128/MCB.22.19.6681-6688.2002. View

12.

Zou H, Henzel W, Liu X, Lutschg A, Wang X . Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell. 1997; 90(3):405-13. DOI: 10.1016/s0092-8674(00)80501-2. View

13.

von Heijne G . Signal sequences. The limits of variation. J Mol Biol. 1985; 184(1):99-105. DOI: 10.1016/0022-2836(85)90046-4. View

14.

Travers K, Patil C, Wodicka L, Lockhart D, Weissman J, Walter P . Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation. Cell. 2000; 101(3):249-58. DOI: 10.1016/s0092-8674(00)80835-1. View

15.

Hollien J, Weissman J . Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science. 2006; 313(5783):104-7. DOI: 10.1126/science.1129631. View

16.

Obacz J, Avril T, Rubio-Patino C, Bossowski J, Igbaria A, Ricci J . Regulation of tumor-stroma interactions by the unfolded protein response. FEBS J. 2017; 286(2):279-296. DOI: 10.1111/febs.14359. View

17.

Gonzalez A, Covarrubias-Pinto A, Bhaskara R, Glogger M, Kuncha S, Xavier A . Ubiquitination regulates ER-phagy and remodelling of endoplasmic reticulum. Nature. 2023; 618(7964):394-401. PMC: 10247366. DOI: 10.1038/s41586-023-06089-2. View

18.

Oyadomari S, Yun C, Fisher E, Kreglinger N, Kreibich G, Oyadomari M . Cotranslocational degradation protects the stressed endoplasmic reticulum from protein overload. Cell. 2006; 126(4):727-39. DOI: 10.1016/j.cell.2006.06.051. View

19.

Akagi S, Yamamoto A, Yoshimori T, Masaki R, Ogawa R, Tashiro Y . Distribution of protein disulfide isomerase in rat hepatocytes. J Histochem Cytochem. 1988; 36(12):1533-42. DOI: 10.1177/36.12.3192937. View

20.

Ciechanover A, Finley D, Varshavsky A . Ubiquitin dependence of selective protein degradation demonstrated in the mammalian cell cycle mutant ts85. Cell. 1984; 37(1):57-66. DOI: 10.1016/0092-8674(84)90300-3. View