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Heritable α1-Antitrypsin Deficiency

  • Chapter
Molecular Pathology of Lung Diseases

Part of the book series: Molecular Pathology Library ((MPLB,volume 1))

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Abstract

A heritable deficiency of circulating α1-antitrypsin (AAT) can lead to the development of pulmonary emphysema in response to the elastolytic destruction of lung connective tissue. Inappropriate accumulation of the molecule in hepatocytes, the primary site of biosynthesis, is an etiologic agent of liver injury. The deficiency results from inappropriate structural maturation of the newly synthesized molecule, whereas defective folding and incomplete clearance lead to intrahepatic accumulation. A small ensemble of processing enzymes modify the asparagines-linked oligosaccharides to generate fate determinants that promote the molecule’s entrance into either pathway. The interconnection of these systems, thought to represent the decentralized surveillance of eukaryotic genome expression, is suspected to contain potential modifiers of both diseases. For this reason, the chapter focuses on the elucidation of cellular strategies used by cells to handle mutant forms of AAT.

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References

  1. Carrell RW, Pemberton PA, Boswell DR. The serpins: evolution and adaptation in a family of protease inhibitors. Cold Spring Harb Symp Quant Biol 1987;52:527–535.

    CAS  PubMed  Google Scholar 

  2. Bao JJ, Sifers RN, Kidd VJ, et al. Molecular evolution of serpins: homologous structure of the human alpha 1-antichymotrypsin and alpha 1-antitrypsin genes. Biochemistry 1987;26(24):7755–7759.

    Article  CAS  PubMed  Google Scholar 

  3. Crowther DC, Belorgey D, Miranda E, et al. Practical genetics: alpha-1-antitrypsin deficiency and the serpinopathies. Eur J Hum Genet 2004;12(3):167–172.

    Article  CAS  PubMed  Google Scholar 

  4. Sifers RN, Finegold MJ, Woo SL. Molecular biology and genetics of alpha 1-antitrypsin deficiency. Semin Liver Dis 1992;12(3):301–310.

    Article  CAS  PubMed  Google Scholar 

  5. Eriksson, S. Studies in alpha 1-antitrypsin deficiency. Acta Med Scand Suppl 1965;432:1–85.

    CAS  PubMed  Google Scholar 

  6. Lomas, DA. Chronic obstructive pulmonary disease. Introduction. Thorax 2002;57(8):735.

    Article  CAS  PubMed  Google Scholar 

  7. Carrell R, Lomas D, Stein P, et al. Dysfunctional variants and the structural biology of the serpins. Adv Exp Med Biol 1997;425:207–22.

    CAS  PubMed  Google Scholar 

  8. Parmar JS, Mahadeva R, Reed BJ, et al. Polymers of alpha(1)-antitrypsin are chemotactic for human neutrophils: a new paradigm for the pathogenesis of emphysema. Am J Respir Cell Mol Biol 2002;26(6):723–730.

    CAS  PubMed  Google Scholar 

  9. Graham KS, Le A, Sifers RN. Accumulation of the insoluble PiZ variant of human alpha 1-antitrypsin within the hepatic endoplasmic reticulum does not elevate the steady-state level of grp78/BiP. J Biol Chem 1990;265(33):20463–8.

    CAS  PubMed  Google Scholar 

  10. Carlson JA, Rogers BB, Sifers RN, et al. Accumulation of PiZ alpha 1-antitrypsin causes liver damage in transgenic mice. J Clin Invest 1989;83(4):1183–1190.

    Article  CAS  PubMed  Google Scholar 

  11. Perlmutter DH. Liver disease associated with alpha 1-antitrypsin deficiency. Prog Liver Dis 1993;11:139–165.

    CAS  PubMed  Google Scholar 

  12. Perlmutter DH. Pathogenesis of chronic liver injury and hepatocellular carcinoma in alpha-1-antitrypsin deficiency. Pediatr Res 2006;60(2):233–238.

    Article  CAS  PubMed  Google Scholar 

  13. Carrell RW, Whisstock J, Lomas DA. Conformational changes in serpins and the mechanism of alpha 1-antitrypsin deficiency. Am J Respir Crit Care Med 1994;150(6 Pt 2):S171–S175.

    CAS  PubMed  Google Scholar 

  14. Lomas DA. Loop-sheet polymerization: the structural basis of Z alpha 1-antitrypsin accumulation in the liver. Clin Sci (Lond) 1994;86(5):489–495.

    CAS  PubMed  Google Scholar 

  15. Lomas DA, Evans DL, Finch JT, et al. The mechanism of Z alpha 1-antitrypsin accumulation in the liver. Nature 1992;357(6379):605–607.

    Article  CAS  PubMed  Google Scholar 

  16. Lomas DA, Mahadeva R, Alpha1-antitrypsin polymerization and the serpinopathies: pathobiology and prospects for therapy. J Clin Invest 2002;110(11):1585–1590.

    CAS  PubMed  Google Scholar 

  17. Mahadeva R, Atkinson C, Li Z, et al. Polymers of Z alpha1-antitrypsin co-localize with neutrophils in emphysematous alveoli and are chemotactic in vivo. Am J Pathol 2005;166(2):377–386.

    CAS  PubMed  Google Scholar 

  18. Le A, Graham KS, Sifers RN. Intracellular degradation of the transport-impaired human PiZ alpha 1-antitrypsin variant. Biochemical mapping of the degradative event among compartments of the secretory pathway. J Biol Chem 1990;265(23):14001–14007.

    CAS  PubMed  Google Scholar 

  19. Sifers RN, Brashears-Macatee S, Kidd VJ, et al. A frame-shift mutation results in a truncated alpha 1-antitrypsin that is retained within the rough endoplasmic reticulum. J Biol Chem 1988;263(15):7330–7335.

    CAS  PubMed  Google Scholar 

  20. Teckman JH, Perlmutter DH. 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):13215–13220.

    Article  CAS  PubMed  Google Scholar 

  21. Qu D, Teckman JH, Perlmutter DH. Review: alpha 1-antitrypsin deficiency associated liver disease. J Gastroenterol Hepatol 1997;12(5):404–416.

    Article  CAS  PubMed  Google Scholar 

  22. Perlmutter DH. Liver injury in alpha 1-antitrypsin deficiency. Clin Liver Dis 2000;4(2):387–408.

    Article  CAS  PubMed  Google Scholar 

  23. Wu Y, Whitman I, Molmenti E, et al. A lag in intracellular degradation of mutant alpha 1-antitrypsin correlates with the liver disease phenotype in homozygous PiZZ alpha 1-antitrypsin deficiency. Proc Natl Acad Sci USA 1994;91(19):9014–9018.

    Article  CAS  PubMed  Google Scholar 

  24. Perlmutter DH. The cellular basis for liver injury in alpha 1-antitrypsin deficiency. Hepatology 1991;13(1):172–185.

    Article  CAS  PubMed  Google Scholar 

  25. Perlmutter DH. Misfolded proteins in the endoplasmic reticulum. Lab Invest 1999;79(6):623–638.

    CAS  PubMed  Google Scholar 

  26. Le A, Ferrell GA, Dishon DS, et al. Soluble aggregates of the human PiZ alpha 1-antitrypsin variant are degraded within the endoplasmic reticulum by a mechanism sensitive to inhibitors of protein synthesis. J Biol Chem 1992;267(2):1072–1080.

    CAS  PubMed  Google Scholar 

  27. Ellgaard L, Helenius A. ER quality control: towards an understanding at the molecular level. Curr Opin Cell Biol 2001;13(4):431–437.

    Article  CAS  PubMed  Google Scholar 

  28. Cabral CM, Liu Y, Sifers RN. Dissecting glycoprotein quality control in the secretory pathway. Trends Biochem Sci 2001;26(10):619–624.

    Article  CAS  PubMed  Google Scholar 

  29. Hammond C, Helenius A. Quality control in the secretory pathway. Curr Opin Cell Biol 1995;7(4):523–529.

    Article  CAS  PubMed  Google Scholar 

  30. Helenius A. Quality control in the secretory assembly line. Philos Trans R Soc Lond B Biol Sci 2001;356(1406):147–150.

    Article  CAS  PubMed  Google Scholar 

  31. Sifers RN. Insights into checkpoint capacity. Nat Struct Mol Biol 2004;11(2):108–109.

    Article  CAS  PubMed  Google Scholar 

  32. Helenius A, Marquardt T, Braakman I. The endoplasmic reticulum as a protein-folding compartment. Trends Cell Biol 1992;2(8):227–231.

    Article  CAS  PubMed  Google Scholar 

  33. Liu Y, Choudhury P, Cabral CM, et al. Intracellular disposal of incompletely folded human alpha1-antitrypsin involves release from calnexin and post-translational trimming of asparagine-linked oligosaccharides. J Biol Chem 1997;272(12):7946–7951.

    Article  CAS  PubMed  Google Scholar 

  34. Cabral CM, Choudhury P, Liu Y, et al. Processing by endoplasmic reticulum mannosidases partitions a secretion-impaired glycoprotein into distinct disposal pathways. J Biol Chem 2000;275(32):25015–25022.

    Article  CAS  PubMed  Google Scholar 

  35. Termine D, Wu Y, Liu Y, et al. Alpha1-antitrypsin as model to assess glycan function in endoplasmic reticulum. Methods 2005;35(4):348–353.

    Article  CAS  PubMed  Google Scholar 

  36. Helenius A. How N-linked oligosaccharides affect glycoprotein folding in the endoplasmic reticulum. Mol Biol Cell 1994;5(3):253–265.

    CAS  PubMed  Google Scholar 

  37. Helenius A, Aebi M. Roles of N-linked glycans in the endoplasmic reticulum. Annu Rev Biochem 2004;73:1019–1049.

    Article  CAS  PubMed  Google Scholar 

  38. Cannon KS, Helenius A. Trimming and readdition of glucose to N-linked oligosaccharides determines calnexin association of a substrate glycoprotein in living cells. J Biol Chem 1999;274(11):7537–7544.

    Article  CAS  PubMed  Google Scholar 

  39. Hebert DN, Foellmer B, Helenius A. Calnexin and calreticulin promote folding, delay oligomerization and suppress degradation of influenza hemagglutinin in microsomes. EMBO J 1996;15(12):2961–2968.

    CAS  PubMed  Google Scholar 

  40. 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 USA 1994;91(3):913–917.

    Article  CAS  PubMed  Google Scholar 

  41. Hebert DN, Foellmer B, Helenius A. Glucose trimming and reglucosylation determine glycoprotein association with calnexin in the endoplasmic reticulum. Cell 1995;81(3):425–433.

    Article  CAS  PubMed  Google Scholar 

  42. Trombetta ES, Helenius A. Conformational requirements for glycoprotein reglucosylation in the endoplasmic reticulum. J Cell Biol 2000;148(6):1123–1129.

    Article  CAS  PubMed  Google Scholar 

  43. Sifers RN, Finegold MJ, Woo SL. Alpha-1-antitrypsin deficiency: accumulation or degradation of mutant variants within the hepatic endoplasmic reticulum. Am J Respir Cell Mol Biol 1989;1(5):341–345.

    CAS  PubMed  Google Scholar 

  44. Le A, Steiner JL, Ferrell GA, et al. Association between calnexin and a secretion-incompetent variant of human alpha 1-antitrypsin. J Biol Chem 1994;269(10):7514–7519.

    CAS  PubMed  Google Scholar 

  45. Wu Y, Swulius MT, Moremen KW, et al. Elucidation of the molecular logic by which misfolded alpha 1-antitrypsin is preferentially selected for degradation. Proc Natl Acad Sci USA 2003;100(14):8229–8234.

    Article  CAS  PubMed  Google Scholar 

  46. Lederkremer GZ, Glickman MH. A window of opportunity: timing protein degradation by trimming of sugars and ubiquitins. Trends Biochem Sci 2005;30(6):297–303.

    Article  CAS  PubMed  Google Scholar 

  47. Kamhi-Nesher S, Shenkman M, Tolchinsky S, et al. A novel quality control compartment derived from the endoplasmic reticulum. Mol Biol Cell 2001;12(6):1711–1723.

    CAS  PubMed  Google Scholar 

  48. Cabral CM, Liu Y, Moremen KW, et al. Organizational diversity among distinct glycoprotein endoplasmic reticulum-associated degradation programs. Mol Biol Cell 2002;13(8):2639–2650.

    Article  CAS  PubMed  Google Scholar 

  49. Teckman JH, Burrows J, Hidvegi T, et al. The proteasome participates in degradation of mutant alpha 1-antitrypsin Z in the endoplasmic reticulum of hepatomaderived hepatocytes. J Biol Chem 2001;276(48):44865–44872.

    Article  CAS  PubMed  Google Scholar 

  50. Zhou A, Stein PE, Huntington JA, et al. How small peptides block and reverse serpin polymerisation. J Mol Biol 2004;342(3):931–941.

    Article  CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Pathology, Baylor College of Medicine, Houston, TX, USA

    Richard N. Sifers PhD (Associate Professor)

Authors
  1. Richard N. Sifers PhD
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Editor information

Editors and Affiliations

  1. Department of Pathology, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA

    Dani S. Zander MD

  2. Institute of Pathology, Laboratories for Molecular Cytogenetics, Medical University of Graz, Graz, Austria

    Helmut H. Popper MD

  3. Department of Pathology, University of Texas Health Science Center, San Antonio, TX, USA

    Jaishree Jagirdar MD

  4. Weill Medical College of Cornell University, New York, NY

    Abida K. Haque MD

  5. Department of Pathology, San Jacinto Methodist Hospital, Baytown, TX, USA

    Abida K. Haque MD

  6. Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY

    Philip T. Cagle MD  & Roberto Barrios MD  & 

  7. The Methodist Hospital, Houston, TX, USA

    Philip T. Cagle MD  & Roberto Barrios MD  & 

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Sifers, R.N. (2008). Heritable α1-Antitrypsin Deficiency. In: Zander, D.S., Popper, H.H., Jagirdar, J., Haque, A.K., Cagle, P.T., Barrios, R. (eds) Molecular Pathology of Lung Diseases. Molecular Pathology Library, vol 1. Springer, New York, NY. https://doi.org/10.1007/978-0-387-72430-0_50

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  • DOI: https://doi.org/10.1007/978-0-387-72430-0_50

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-0-387-72429-4

  • Online ISBN: 978-0-387-72430-0

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