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. 1998 Jun 15;101(12):2900–2909. doi: 10.1172/JCI2649

A novel form of hereditary myeloperoxidase deficiency linked to endoplasmic reticulum/proteasome degradation.

F R DeLeo 1, M Goedken 1, S J McCormick 1, W M Nauseef 1
PMCID: PMC508882  PMID: 9637725

Abstract

Myeloperoxidase (MPO) deficiency is a common inherited disorder linked to increased susceptibility to infection and malignancy. We identified a novel missense mutation in the MPO gene at codon 173 whereby tyrosine is replaced with cysteine (Y173C) that is associated with MPO deficiency and assessed its impact on MPO processing and targeting in transfectants expressing normal or mutant proteins. Although the precursor synthesized by cells expressing the Y173C mutation (MPOY173C) was glycosylated, associated with the molecular chaperones calreticulin and calnexin, and acquired heme, it was neither proteolytically processed to mature MPO subunits nor secreted. After prolonged association with calreticulin and calnexin in the endoplasmic reticulum, MPOY173C was degraded. Furthermore, the 20S proteasome inhibitor N-acetyl-L-leucinyl-L-leucinyl-L-norleucinyl inhibited its degradation, suggesting that the proteasome mediates proteolysis of MPOY173C and, thus, participates in quality control in this novel form of hereditary MPO deficiency.

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Selected References

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  1. Akin D. T., Kinkade J. M., Jr, Parmley R. T. Biochemical and ultrastructural effects of monensin on the processing, intracellular transport, and packaging of myeloperoxidase into low and high density compartments of human leukemia (HL-60) cells. Arch Biochem Biophys. 1987 Sep;257(2):451–463. doi: 10.1016/0003-9861(87)90590-x. [DOI] [PubMed] [Google Scholar]
  2. Arnljots K., Olsson I. Myeloperoxidase precursors incorporate heme. J Biol Chem. 1987 Aug 5;262(22):10430–10433. [PubMed] [Google Scholar]
  3. Borregaard N., Heiple J. M., Simons E. R., Clark R. A. Subcellular localization of the b-cytochrome component of the human neutrophil microbicidal oxidase: translocation during activation. J Cell Biol. 1983 Jul;97(1):52–61. doi: 10.1083/jcb.97.1.52. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Böyum A. Isolation of mononuclear cells and granulocytes from human blood. Isolation of monuclear cells by one centrifugation, and of granulocytes by combining centrifugation and sedimentation at 1 g. Scand J Clin Lab Invest Suppl. 1968;97:77–89. [PubMed] [Google Scholar]
  5. Castañeda V. L., Parmley R. T., Pinnix I. B., Raju S. G., Guzman G. S., Kinkade J. M., Jr Ultrastructural, immunochemical, and cytochemical study of myeloperoxidase in myeloid leukemia HL-60 cells following treatment with succinylacetone, an inhibitor of heme biosynthesis. Exp Hematol. 1992 Aug;20(7):916–924. [PubMed] [Google Scholar]
  6. Cross A. R., Curnutte J. T., Rae J., Heyworth P. G. Hematologically important mutations: X-linked chronic granulomatous disease. Blood Cells Mol Dis. 1996;22(1):90–95. doi: 10.1006/bcmd.1996.0013. [DOI] [PubMed] [Google Scholar]
  7. Hazen S. L., Hsu F. F., Duffin K., Heinecke J. W. Molecular chlorine generated by the myeloperoxidase-hydrogen peroxide-chloride system of phagocytes converts low density lipoprotein cholesterol into a family of chlorinated sterols. J Biol Chem. 1996 Sep 20;271(38):23080–23088. doi: 10.1074/jbc.271.38.23080. [DOI] [PubMed] [Google Scholar]
  8. Hazen S. L., Hsu F. F., Mueller D. M., Crowley J. R., Heinecke J. W. Human neutrophils employ chlorine gas as an oxidant during phagocytosis. J Clin Invest. 1996 Sep 15;98(6):1283–1289. doi: 10.1172/JCI118914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hiller M. M., Finger A., Schweiger M., Wolf D. H. ER degradation of a misfolded luminal protein by the cytosolic ubiquitin-proteasome pathway. Science. 1996 Sep 20;273(5282):1725–1728. doi: 10.1126/science.273.5282.1725. [DOI] [PubMed] [Google Scholar]
  10. Hur S. J., Toda H. K., Yamada M. Isolation and characterization of an unprocessed extracellular myeloperoxidase in HL-60 cell cultures. J Biol Chem. 1989 May 25;264(15):8542–8548. [PubMed] [Google Scholar]
  11. Jensen T. J., Loo M. A., Pind S., Williams D. B., Goldberg A. L., Riordan J. R. Multiple proteolytic systems, including the proteasome, contribute to CFTR processing. Cell. 1995 Oct 6;83(1):129–135. doi: 10.1016/0092-8674(95)90241-4. [DOI] [PubMed] [Google Scholar]
  12. Klebanoff S. J., Hamon C. B. Role of myeloperoxidase-mediated antimicrobial systems in intact leukocytes. J Reticuloendothel Soc. 1972 Aug;12(2):170–196. [PubMed] [Google Scholar]
  13. Klebanoff S. J. Myeloperoxidase: contribution to the microbicidal activity of intact leukocytes. Science. 1970 Sep 11;169(3950):1095–1097. doi: 10.1126/science.169.3950.1095. [DOI] [PubMed] [Google Scholar]
  14. Kopito R. R. ER quality control: the cytoplasmic connection. Cell. 1997 Feb 21;88(4):427–430. doi: 10.1016/s0092-8674(00)81881-4. [DOI] [PubMed] [Google Scholar]
  15. Lozzio B. B., Lozzio C. B. Properties and usefulness of the original K-562 human myelogenous leukemia cell line. Leuk Res. 1979;3(6):363–370. doi: 10.1016/0145-2126(79)90033-x. [DOI] [PubMed] [Google Scholar]
  16. Nauseef W. M., Brigham S., Cogley M. Hereditary myeloperoxidase deficiency due to a missense mutation of arginine 569 to tryptophan. J Biol Chem. 1994 Jan 14;269(2):1212–1216. [PubMed] [Google Scholar]
  17. Nauseef W. M., Clark R. A. Separation and analysis of subcellular organelles in a human promyelocytic leukemia cell line, HL-60: application to the study of myeloid lysosomal enzyme synthesis and processing. Blood. 1986 Aug;68(2):442–449. [PubMed] [Google Scholar]
  18. Nauseef W. M., Cogley M., McCormick S. Effect of the R569W missense mutation on the biosynthesis of myeloperoxidase. J Biol Chem. 1996 Apr 19;271(16):9546–9549. doi: 10.1074/jbc.271.16.9546. [DOI] [PubMed] [Google Scholar]
  19. Nauseef W. M., McCormick S. J., Clark R. A. Calreticulin functions as a molecular chaperone in the biosynthesis of myeloperoxidase. J Biol Chem. 1995 Mar 3;270(9):4741–4747. doi: 10.1074/jbc.270.9.4741. [DOI] [PubMed] [Google Scholar]
  20. Nauseef W. M., McCormick S. J., Goedken M. Coordinated participation of calreticulin and calnexin in the biosynthesis of myeloperoxidase. J Biol Chem. 1998 Mar 20;273(12):7107–7111. doi: 10.1074/jbc.273.12.7107. [DOI] [PubMed] [Google Scholar]
  21. Nauseef W. M., McCormick S., Yi H. Roles of heme insertion and the mannose-6-phosphate receptor in processing of the human myeloid lysosomal enzyme, myeloperoxidase. Blood. 1992 Nov 15;80(10):2622–2633. [PubMed] [Google Scholar]
  22. Nauseef W. M. Myeloperoxidase biosynthesis by a human promyelocytic leukemia cell line: insight into myeloperoxidase deficiency. Blood. 1986 Apr;67(4):865–872. [PubMed] [Google Scholar]
  23. Nauseef W. M. Myeloperoxidase deficiency. Hematol Pathol. 1990;4(4):165–178. [PubMed] [Google Scholar]
  24. Nauseef W. M., Olsson I., Arnljots K. Biosynthesis and processing of myeloperoxidase--a marker for myeloid cell differentiation. Eur J Haematol. 1988 Feb;40(2):97–110. doi: 10.1111/j.1600-0609.1988.tb00805.x. [DOI] [PubMed] [Google Scholar]
  25. Ou W. J., Cameron P. H., Thomas D. Y., Bergeron J. J. Association of folding intermediates of glycoproteins with calnexin during protein maturation. Nature. 1993 Aug 26;364(6440):771–776. doi: 10.1038/364771a0. [DOI] [PubMed] [Google Scholar]
  26. Pinnix I. B., Guzman G. S., Bonkovsky H. L., Zaki S. R., Kinkade J. M., Jr The post-translational processing of myeloperoxidase is regulated by the availability of heme. Arch Biochem Biophys. 1994 Aug 1;312(2):447–458. doi: 10.1006/abbi.1994.1331. [DOI] [PubMed] [Google Scholar]
  27. Robinson J. M., Badwey J. A. The NADPH oxidase complex of phagocytic leukocytes: a biochemical and cytochemical view. Histochem Cell Biol. 1995 Mar;103(3):163–180. doi: 10.1007/BF01454021. [DOI] [PubMed] [Google Scholar]
  28. Sottocasa G. L., Kuylenstierna B., Ernster L., Bergstrand A. An electron-transport system associated with the outer membrane of liver mitochondria. A biochemical and morphological study. J Cell Biol. 1967 Feb;32(2):415–438. doi: 10.1083/jcb.32.2.415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Thrasher A. J., Keep N. H., Wientjes F., Segal A. W. Chronic granulomatous disease. Biochim Biophys Acta. 1994 Oct 21;1227(1-2):1–24. doi: 10.1016/0925-4439(94)90100-7. [DOI] [PubMed] [Google Scholar]
  30. Tobler A., Selsted M. E., Miller C. W., Johnson K. R., Novotny M. J., Rovera G., Koeffler H. P. Evidence for a pretranslational defect in hereditary and acquired myeloperoxidase deficiency. Blood. 1989 May 15;73(7):1980–1986. [PubMed] [Google Scholar]
  31. Tucker K. A., Lilly M. B., Heck L., Jr, Rado T. A. Characterization of a new human diploid myeloid leukemia cell line (PLB-985) with granulocytic and monocytic differentiating capacity. Blood. 1987 Aug;70(2):372–378. [PubMed] [Google Scholar]
  32. Ward C. L., Omura S., Kopito R. R. Degradation of CFTR by the ubiquitin-proteasome pathway. Cell. 1995 Oct 6;83(1):121–127. doi: 10.1016/0092-8674(95)90240-6. [DOI] [PubMed] [Google Scholar]
  33. Werner E. D., Brodsky J. L., McCracken A. A. Proteasome-dependent endoplasmic reticulum-associated protein degradation: an unconventional route to a familiar fate. Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13797–13801. doi: 10.1073/pnas.93.24.13797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Wright A. H., Douglass W. A., Taylor G. M., Lau Y. L., Higgins D., Davies K. A., Law S. K. Molecular characterization of leukocyte adhesion deficiency in six patients. Eur J Immunol. 1995 Mar;25(3):717–722. doi: 10.1002/eji.1830250313. [DOI] [PubMed] [Google Scholar]
  35. Zeng J., Fenna R. E. X-ray crystal structure of canine myeloperoxidase at 3 A resolution. J Mol Biol. 1992 Jul 5;226(1):185–207. doi: 10.1016/0022-2836(92)90133-5. [DOI] [PubMed] [Google Scholar]

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