N-glycan Processing Selects ERAD-resistant Misfolded Proteins for ER-to-lysosome-associated Degradation

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2021 Jun 21

PMID 34152647

Citations 24

Authors

Ilaria Fregno

Elisa Fasana

Tatiana Solda

Carmela Galli

Maurizio Molinari

Affiliations

Soon will be listed here.

Abstract

Efficient degradation of by-products of protein biogenesis maintains cellular fitness. Strikingly, the major biosynthetic compartment in eukaryotic cells, the endoplasmic reticulum (ER), lacks degradative machineries. Misfolded proteins in the ER are translocated to the cytosol for proteasomal degradation via ER-associated degradation (ERAD). Alternatively, they are segregated in ER subdomains that are shed from the biosynthetic compartment and are delivered to endolysosomes under control of ER-phagy receptors for ER-to-lysosome-associated degradation (ERLAD). Demannosylation of N-linked oligosaccharides targets terminally misfolded proteins for ERAD. How misfolded proteins are eventually marked for ERLAD is not known. Here, we show for ATZ and mutant Pro-collagen that cycles of de-/re-glucosylation of selected N-glycans and persistent association with Calnexin (CNX) are required and sufficient to mark ERAD-resistant misfolded proteins for FAM134B-driven lysosomal delivery. In summary, we show that mannose and glucose processing of N-glycans are triggering events that target misfolded proteins in the ER to proteasomal (ERAD) and lysosomal (ERLAD) clearance, respectively, regulating protein quality control in eukaryotic cells.

Citing Articles

Endoplasmic reticulum stress-mediated apoptosis and autophagy in osteoarthritis: From molecular mechanisms to therapeutic applications.

Lu Y, Zhou J, Wang H, Gao H, Ning E, Shao Z Cell Stress Chaperones. 2024; 29(6):805-830.

PMID: 39571722 PMC: 11667160. DOI: 10.1016/j.cstres.2024.11.005.

Mutations in fibronectin dysregulate chondrogenesis in skeletal dysplasia.

Dinesh N, Rousseau J, Mosher D, Strauss M, Mui J, Campeau P Cell Mol Life Sci. 2024; 81(1):419.

PMID: 39367925 PMC: 11456097. DOI: 10.1007/s00018-024-05444-4.

An Essential Role for Calnexin in ER-Phagy and the Unfolded Protein Response.

Wolf D, Roder C, Sendtner M, Luningschror P Cells. 2024; 13(17.

PMID: 39273068 PMC: 11394613. DOI: 10.3390/cells13171498.

Time-resolved interactome profiling deconvolutes secretory protein quality control dynamics.

Wright M, Timalsina B, Garcia Lopez V, Hermanson J, Garcia S, Plate L Mol Syst Biol. 2024; 20(9):1049-1075.

PMID: 39103653 PMC: 11369088. DOI: 10.1038/s44320-024-00058-1.

Sestrin2 drives ER-phagy in response to protein misfolding.

De Leonibus C, Maddaluno M, Ferriero R, Besio R, Cinque L, Lim P Dev Cell. 2024; 59(16):2035-2052.e10.

PMID: 39094564 PMC: 11338521. DOI: 10.1016/j.devcel.2024.07.004.

References

Hosokawa N, Kamiya Y, Kamiya D, Kato K, Nagata K . Human OS-9, a lectin required for glycoprotein endoplasmic reticulum-associated degradation, recognizes mannose-trimmed N-glycans. J Biol Chem. 2009; 284(25):17061-17068. PMC: 2719344. DOI: 10.1074/jbc.M809725200. View

Perlmutter D . Alpha-1-antitrypsin deficiency: importance of proteasomal and autophagic degradative pathways in disposal of liver disease-associated protein aggregates. Annu Rev Med. 2010; 62:333-45. DOI: 10.1146/annurev-med-042409-151920. View

Loi M, Molinari M . Mechanistic insights in recov-ER-phagy: micro-ER-phagy to recover from stress. Autophagy. 2020; 16(2):385-386. PMC: 6984597. DOI: 10.1080/15548627.2019.1709767. View

Smith M, Harley M, Kemp A, Wills J, Lee M, Arends M . CCPG1 Is a Non-canonical Autophagy Cargo Receptor Essential for ER-Phagy and Pancreatic ER Proteostasis. Dev Cell. 2018; 44(2):217-232.e11. PMC: 5791736. DOI: 10.1016/j.devcel.2017.11.024. View

Fregno I, Fasana E, Bergmann T, Raimondi A, Loi M, Solda T . ER-to-lysosome-associated degradation of proteasome-resistant ATZ polymers occurs via receptor-mediated vesicular transport. EMBO J. 2018; 37(17). PMC: 6120659. DOI: 10.15252/embj.201899259. View

Khaminets A, Heinrich T, Mari M, Grumati P, Huebner A, Akutsu M . Regulation of endoplasmic reticulum turnover by selective autophagy. Nature. 2015; 522(7556):354-8. DOI: 10.1038/nature14498. View

Chino H, Hatta T, Natsume T, Mizushima N . Intrinsically Disordered Protein TEX264 Mediates ER-phagy. Mol Cell. 2019; 74(5):909-921.e6. DOI: 10.1016/j.molcel.2019.03.033. View

Hammond C, Braakman I, Helenius A . Role of N-linked oligosaccharide recognition, glucose trimming, and calnexin in glycoprotein folding and quality control. Proc Natl Acad Sci U S A. 1994; 91(3):913-7. PMC: 521423. DOI: 10.1073/pnas.91.3.913. View

Fumagalli F, Noack J, Bergmann T, Cebollero E, Pisoni G, Fasana E . Translocon component Sec62 acts in endoplasmic reticulum turnover during stress recovery. Nat Cell Biol. 2016; 18(11):1173-1184. DOI: 10.1038/ncb3423. View

10.

Helenius A . How N-linked oligosaccharides affect glycoprotein folding in the endoplasmic reticulum. Mol Biol Cell. 1994; 5(3):253-65. PMC: 301034. DOI: 10.1091/mbc.5.3.253. View

11.

Wilkinson S . Emerging Principles of Selective ER Autophagy. J Mol Biol. 2019; 432(1):185-205. PMC: 6971691. DOI: 10.1016/j.jmb.2019.05.012. View

12.

Bernasconi R, Galli C, Calanca V, Nakajima T, Molinari M . Stringent requirement for HRD1, SEL1L, and OS-9/XTP3-B for disposal of ERAD-LS substrates. J Cell Biol. 2010; 188(2):223-35. PMC: 2812524. DOI: 10.1083/jcb.200910042. View

13.

Teckman J, Perlmutter D . The endoplasmic reticulum degradation pathway for mutant secretory proteins alpha1-antitrypsin Z and S is distinct from that for an unassembled membrane protein. J Biol Chem. 1996; 271(22):13215-20. DOI: 10.1074/jbc.271.22.13215. View

14.

Kraus A, Groenendyk J, Bedard K, Baldwin T, Krause K, Dubois-Dauphin M . Calnexin deficiency leads to dysmyelination. J Biol Chem. 2010; 285(24):18928-38. PMC: 2881815. DOI: 10.1074/jbc.M110.107201. View

15.

Leto D, Morgens D, Zhang L, Walczak C, Elias J, Bassik M . Genome-wide CRISPR Analysis Identifies Substrate-Specific Conjugation Modules in ER-Associated Degradation. Mol Cell. 2018; 73(2):377-389.e11. PMC: 6338494. DOI: 10.1016/j.molcel.2018.11.015. View

16.

Bhamidipati A, Denic V, Quan E, Weissman J . Exploration of the topological requirements of ERAD identifies Yos9p as a lectin sensor of misfolded glycoproteins in the ER lumen. Mol Cell. 2005; 19(6):741-51. DOI: 10.1016/j.molcel.2005.07.027. View

17.

Bernasconi R, Pertel T, Luban J, Molinari M . A dual task for the Xbp1-responsive OS-9 variants in the mammalian endoplasmic reticulum: inhibiting secretion of misfolded protein conformers and enhancing their disposal. J Biol Chem. 2008; 283(24):16446-54. PMC: 3762559. DOI: 10.1074/jbc.M802272200. View

18.

Molinari M, Galli C, Piccaluga V, Pieren M, Paganetti P . Sequential assistance of molecular chaperones and transient formation of covalent complexes during protein degradation from the ER. J Cell Biol. 2002; 158(2):247-57. PMC: 2173128. DOI: 10.1083/jcb.200204122. View

19.

Elbein A . Glycosidase inhibitors: inhibitors of N-linked oligosaccharide processing. FASEB J. 1991; 5(15):3055-63. DOI: 10.1096/fasebj.5.15.1743438. View

20.

Olivari S, Molinari M . Glycoprotein folding and the role of EDEM1, EDEM2 and EDEM3 in degradation of folding-defective glycoproteins. FEBS Lett. 2007; 581(19):3658-64. DOI: 10.1016/j.febslet.2007.04.070. View