The Role of UDP-Glc:glycoprotein Glucosyltransferase 1 in the Maturation of an Obligate Substrate Prosaposin

Overview

Journal J Cell Biol

Specialty Cell Biology

Date 2010 May 26

PMID 20498017

Citations 23

Authors

Bradley R Pearse

Taku Tamura

Johan C Sunryd

Gregory A Grabowski

Randal J Kaufman

Daniel N Hebert

Affiliations

Soon will be listed here.

Abstract

An endoplasmic reticulum (ER) quality control system assists in efficient folding and disposal of misfolded proteins. N-linked glycans are critical in these events because their composition dictates interactions with molecular chaperones. UDP-glucose:glycoprotein glucosyltransferase 1 (UGT1) is a key quality control factor of the ER. It adds glucoses to N-linked glycans of nonglucosylated substrates that fail a quality control test, supporting additional rounds of chaperone binding and ER retention. How UGT1 functions in its native environment is poorly understood. The role of UGT1 in the maturation of glycoproteins at basal expression levels was analyzed. Prosaposin was identified as a prominent endogenous UGT1 substrate. A dramatic decrease in the secretion of prosaposin was observed in ugt1(-/-) cells with prosaposin localized to large juxtanuclear aggresome-like inclusions, which is indicative of its misfolding and the essential role that UGT1 plays in its proper maturation. A model is proposed that explains how UGT1 may aid in the folding of sequential domain-containing proteins such as prosaposin.

Citing Articles

UGGT1-mediated reglucosylation of -glycan competes with ER-associated degradation of unstable and misfolded glycoproteins.

Ninagawa S, Matsuo M, Ying D, Oshita S, Aso S, Matsushita K Elife. 2024; 12.

PMID: 39654396 PMC: 11630818. DOI: 10.7554/eLife.93117.

Rescue of secretion of rare-disease-associated misfolded mutant glycoproteins in UGGT1 knock-out mammalian cells.

Tax G, Guay K, Pantalone L, Ceci M, Solda T, Hitchman C Traffic. 2024; 25(1):e12927.

PMID: 38272446 PMC: 10832616. DOI: 10.1111/tra.12927.

ER chaperones use a protein folding and quality control glyco-code.

Guay K, Ke H, Canniff N, George G, Eyles S, Mariappan M Mol Cell. 2023; 83(24):4524-4537.e5.

PMID: 38052210 PMC: 10790639. DOI: 10.1016/j.molcel.2023.11.006.

Rescue of secretion of a rare-disease associated mis-folded mutant glycoprotein in knock-out mammalian cells.

Tax G, Guay K, Solda T, Hitchman C, Hill J, Vasiljevic S bioRxiv. 2023; .

PMID: 37398215 PMC: 10312515. DOI: 10.1101/2023.05.30.542711.

Quantitative glycoproteomics reveals cellular substrate selectivity of the ER protein quality control sensors UGGT1 and UGGT2.

Adams B, Canniff N, Guay K, Larsen I, Hebert D Elife. 2020; 9.

PMID: 33320095 PMC: 7771966. DOI: 10.7554/eLife.63997.

References

Parodi A, Mendelzon D, Lederkremer G . Evidence that transient glucosylation of protein-linked Man9GlcNAc2, Man8GlcNAc2, and Man7GlcNAc2 occurs in rat liver and Phaseolus vulgaris cells. J Biol Chem. 1984; 259(10):6351-7. View

Hiraiwa M, Soeda S, Martin B, Fluharty A, Hirabayashi Y, OBrien J . The effect of carbohydrate removal on stability and activity of saposin B. Arch Biochem Biophys. 1993; 303(2):326-31. DOI: 10.1006/abbi.1993.1291. View

Chen W, Helenius J, Braakman I, Helenius A . Cotranslational folding and calnexin binding during glycoprotein synthesis. Proc Natl Acad Sci U S A. 1995; 92(14):6229-33. PMC: 41491. DOI: 10.1073/pnas.92.14.6229. View

Ruiz-Canada C, Kelleher D, Gilmore R . Cotranslational and posttranslational N-glycosylation of polypeptides by distinct mammalian OST isoforms. Cell. 2009; 136(2):272-83. PMC: 2859625. DOI: 10.1016/j.cell.2008.11.047. View

Farhan H, Weiss M, Tani K, Kaufman R, Hauri H . Adaptation of endoplasmic reticulum exit sites to acute and chronic increases in cargo load. EMBO J. 2008; 27(15):2043-54. PMC: 2516884. DOI: 10.1038/emboj.2008.136. View

Kishimoto Y, Hiraiwa M, OBrien J . Saposins: structure, function, distribution, and molecular genetics. J Lipid Res. 1992; 33(9):1255-67. View

Johnston J, Ward C, Kopito R . Aggresomes: a cellular response to misfolded proteins. J Cell Biol. 1998; 143(7):1883-98. PMC: 2175217. DOI: 10.1083/jcb.143.7.1883. View

Hebert D, Molinari M . In and out of the ER: protein folding, quality control, degradation, and related human diseases. Physiol Rev. 2007; 87(4):1377-408. DOI: 10.1152/physrev.00050.2006. 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

10.

Rossmann M, Schultz-Heienbrok R, Behlke J, Remmel N, Alings C, Sandhoff K . Crystal structures of human saposins C andD: implications for lipid recognition and membrane interactions. Structure. 2008; 16(5):809-17. DOI: 10.1016/j.str.2008.02.016. View

11.

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

12.

Fernandez F, DAlessio C, Fanchiotti S, Parodi A . A misfolded protein conformation is not a sufficient condition for in vivo glucosylation by the UDP-Glc:glycoprotein glucosyltransferase. EMBO J. 1998; 17(20):5877-86. PMC: 1170915. DOI: 10.1093/emboj/17.20.5877. View

13.

Vassilakos A, Peterson P, Jackson M, Williams D . The molecular chaperone calnexin facilitates folding and assembly of class I histocompatibility molecules. EMBO J. 1996; 15(7):1495-506. PMC: 450057. View

14.

Griswold M, Roberts K, Bishop P . Purification and characterization of a sulfated glycoprotein secreted by Sertoli cells. Biochemistry. 1986; 25(23):7265-70. DOI: 10.1021/bi00371a003. View

15.

Sun Y, Witte D, Zamzow M, Ran H, Quinn B, Matsuda J . Combined saposin C and D deficiencies in mice lead to a neuronopathic phenotype, glucosylceramide and alpha-hydroxy ceramide accumulation, and altered prosaposin trafficking. Hum Mol Genet. 2007; 16(8):957-71. DOI: 10.1093/hmg/ddm040. View

16.

Morales C, Zhao Q, El-Alfy M, Suzuki K . Targeted disruption of the mouse prosaposin gene affects the development of the prostate gland and other male reproductive organs. J Androl. 2000; 21(6):765-75. View

17.

Peterson J, Ora A, Van P, Helenius A . Transient, lectin-like association of calreticulin with folding intermediates of cellular and viral glycoproteins. Mol Biol Cell. 1995; 6(9):1173-84. PMC: 301275. DOI: 10.1091/mbc.6.9.1173. View

18.

Arnold S, Kaufman R . The noncatalytic portion of human UDP-glucose: glycoprotein glucosyltransferase I confers UDP-glucose binding and transferase function to the catalytic domain. J Biol Chem. 2003; 278(44):43320-8. DOI: 10.1074/jbc.M305800200. View

19.

Pearse B, Gabriel L, Wang N, Hebert D . A cell-based reglucosylation assay demonstrates the role of GT1 in the quality control of a maturing glycoprotein. J Cell Biol. 2008; 181(2):309-20. PMC: 2315677. DOI: 10.1083/jcb.200712068. View

20.

Clark P . Protein folding in the cell: reshaping the folding funnel. Trends Biochem Sci. 2004; 29(10):527-34. DOI: 10.1016/j.tibs.2004.08.008. View