Glucosidase and Mannosidase Inhibitors Mediate Increased Secretion of Mutant α1 Antitrypsin Z

It is now well known that the addition and trimming of oligosaccharide side chains during post-translational modification play an important role in determining the fate of secretory, membrane, and lysosomal glycoproteins. Recent studies have suggested that trimming of oligosaccharide side chains also plays a role in the degradation of misfolded glycoproteins as a part of the quality control mechanism of the endoplasmic reticulum (ER). In this study, we examined the effect of several inhibitors of carbohydrate processing on the fate of the misfolded secretory protein α1 antitrypsin Z. Retention of this misfolded glycoprotein in the ER of liver cells in the classical form of α1 antitrypsin (α1-AT) deficiency is associated with severe liver injury and hepatocellular carcinoma and lack of its secretion is associated with destructive lung disease/emphysema. The results show marked alterations in the fate of α1 antitrypsin Z (α1-ATZ). Indeed, one glucosidase inhibitor, castanospermine (CST), and two mannosidase inhibitors, kifunensine (KIF) and deoxymannojirimycin (DMJ), mediate marked increases in secretion of α1-ATZ by distinct mechanisms. The effects of these inhibitors on secretion have interesting implications for our understanding of the quality control apparatus of the ER. These inhibitors may also constitute models for development of additional drugs for chemoprophylaxis of liver injury and emphysema in patients with α1-AT deficiency. It is now well known that the addition and trimming of oligosaccharide side chains during post-translational modification play an important role in determining the fate of secretory, membrane, and lysosomal glycoproteins. Recent studies have suggested that trimming of oligosaccharide side chains also plays a role in the degradation of misfolded glycoproteins as a part of the quality control mechanism of the endoplasmic reticulum (ER). In this study, we examined the effect of several inhibitors of carbohydrate processing on the fate of the misfolded secretory protein α1 antitrypsin Z. Retention of this misfolded glycoprotein in the ER of liver cells in the classical form of α1 antitrypsin (α1-AT) deficiency is associated with severe liver injury and hepatocellular carcinoma and lack of its secretion is associated with destructive lung disease/emphysema. The results show marked alterations in the fate of α1 antitrypsin Z (α1-ATZ). Indeed, one glucosidase inhibitor, castanospermine (CST), and two mannosidase inhibitors, kifunensine (KIF) and deoxymannojirimycin (DMJ), mediate marked increases in secretion of α1-ATZ by distinct mechanisms. The effects of these inhibitors on secretion have interesting implications for our understanding of the quality control apparatus of the ER. These inhibitors may also constitute models for development of additional drugs for chemoprophylaxis of liver injury and emphysema in patients with α1-AT deficiency. endoplasmic reticulum α1 antitrypsin α1 antitrypsin Z kifunensine deoxymannojirimycin castanospermine N-methyldeoxynojirimycin 1,4-dideoxy-1,4-imino-d-mannitol hydrochloride endoglycosidase H N-glycosidase F polyacrylamide gel electrophoresis Dulbecco's modified Eagle's medium extracellular fluid cell lysate(s) 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid phenylmethylsulfonyl fluoride phenylbutyric acid Recent studies have provided further evidence that asparagine-linked oligosaccharide side chains play an important role in intracellular transport of glycoproteins. For one, mannose-6-phosphate modification is a key determinant of sorting to the lysosome (1.Kornfeld S. Mellman I. Annu. Rev. Cell Biol. 1989; 5: 483-525Crossref PubMed Scopus (1235) Google Scholar). Second, a number of studies have now shown that transport of secretory and membrane glycoproteins from the ER1 to their appropriate destination depends on the interaction of the innermost glucose residue of the oligosaccharide side chains with the resident ER molecular chaperones calnexin and calreticulin (2.Helenius A. Trombetta E.S. Hebert D.N. Simons J.F. Trends Cell Biol. 1997; 7: 193-200Abstract Full Text PDF PubMed Scopus (345) Google Scholar, 3.Zapun A. Petrescu S.M. Rudd P.M. Dwek R.A. Thomas D.Y. Bergeron J.J.M. Cell. 1997; 88: 29-38Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar). This means that trimming of the N-glycan by glucosidases I and II and interaction with calnexin and calreticulin facilitate the proper folding and translocation of wild type glycoproteins. There is also evidence that trimming of glucose residues by glucosidases and of mannose residues by ER mannosidases is involved in the degradation of misfolded, unassembled, or mutant glycoproteins (4.Liu Y. Choudhury P. Cabral C.M. Sifers R.N. J. Biol. Chem. 1997; 272: 7946-7951Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, 5.Liu Y. Choudhury P. Cabral C.M. Sifers R.N. J. Biol. Chem. 1999; 274: 5861-5867Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar, 6.Jakob C.A. Burda P. Roth J. Aebi M. J. Cell Biol. 1998; 142: 1223-1233Crossref PubMed Scopus (303) Google Scholar, 7.Kearse K.P. Williams D.B. Singer A. EMBO J. 1994; 13: 3678-3686Crossref PubMed Scopus (111) Google Scholar, 8.Moore S. Spiro R. J. Biol. Chem. 1993; 268: 3809-3813Abstract Full Text PDF PubMed Google Scholar, 9.Yang M. Omura S. Bonifacino J.S. Weissman A.M. J. Exp. Med. 1998; 187: 835-846Crossref PubMed Scopus (202) Google Scholar, 10.Vierhoeven A.J.M. Neve B.P. Jansen H. Biochem. J. 1999; 337: 133-140Crossref PubMed Google Scholar). Third, Nichols et al. (11.Nichols W.C. Seligsohn U. Zivelin A. Terry V.H. Hertel C.E. Wheatley M.A. Moussalli M.J. Hauri H.-P. Ciavarella N. Kaufman R.J. Ginsburg D. Cell. 1998; 93: 61-70Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar) have shown that ERGIC-53, a lectin which is specifically localized in the ER-Golgi intermediate compartment, is mutated in the combined deficiency of coagulation factors V and VIII. These results suggest that a lectin-like mechanism involving the interaction of carbohydrate side chains with ERGIC-53 is required for secretion of factors V and VIII. In the classic type of α1 antitrypsin (α1-AT) deficiency, the most common genetic cause of emphysema in adults and of liver disease in children, the mutant glycoprotein α1-ATZ is retained in the ER of liver cells rather than secreted into the extracellular fluid (12.Teckman J. Qu D. Perlmutter D.H. Hepatology. 1996; 24: 1504-1516PubMed Google Scholar). The mutant α1-ATZ molecule is characterized by a single amino acid substitution, which results in its polymerization in the ER (13.Lomas D.A. Evans D.L. Finch J.J. Carrell R.W. Nature. 1992; 357: 605-607Crossref PubMed Scopus (899) Google Scholar, 14.Yu M.-H. Lee K.N. Kim J. Nat. Struct. Biol. 1995; 2: 363-367Crossref PubMed Scopus (141) Google Scholar). However, the mutant protein retains ∼80% of the functional activity of its wild type counterpart, inhibition of neutrophil elastase (15.Bathurst I.C. Travis J. George P.M. Carrell R.W. FEBS Lett. 1984; 177: 179-183Crossref PubMed Scopus (46) Google Scholar,16.Ogushi F. Fells G.A. Hubbard R.C. Straus S.D. Crystal R.G. J. Clin. Invest. 1987; 89: 1366-1374Crossref Scopus (159) Google Scholar). Because of the lack of this elastase inhibitor in the lung, deficient individuals often develop destructive lung disease/emphysema (12.Teckman J. Qu D. Perlmutter D.H. Hepatology. 1996; 24: 1504-1516PubMed Google Scholar). A subgroup of α1-AT-deficient individuals, predominantly infants and children, also develop chronic liver disease apparently because of the hepatotoxic effect of the mutant α1-ATZ molecule retained in the ER (12.Teckman J. Qu D. Perlmutter D.H. Hepatology. 1996; 24: 1504-1516PubMed Google Scholar). Recent studies have indicated that this subgroup is “susceptible” to liver injury by virtue of a lag in ER degradation resulting in greater accumulation of the misfolded hepatotoxic α1-ATZ molecule in liver cells (17.Wu Y. Whitman I. Molmenti E. Moore K. Hippenmeyer P. Perlmutter D.H. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 9014-9018Crossref PubMed Scopus (234) Google Scholar). There are at least two and perhaps more pathways responsible for degradation of α1-ATZ in the ER. One pathway involves stable binding of α1-ATZ to calnexin, conjugation of ubiquitin to the cytoplasmic tail of complexed calnexin, and degradation of the α1-ATZ-polyubiquitinated calnexin complex by the proteasome (18.Qu D. Teckman J.H. Omura S. Perlmutter D.H. J. Biol. Chem. 1996; 271: 22791-22795Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar). There also appears to be a ubiquitin-independent proteasomal mechanism for degradation of α1-ATZ in the ER (19.Teckman, J. H., Gilmore, R., and Perlmutter, D. H. (1999) Am. J. Physiol., in pressGoogle Scholar). In the current study, we used glucosidase and mannosidase inhibitors to examine the role of oligosaccharide side chain trimming in the fate of α1-ATZ. Previous studies have shown that glucosidase and mannosidase inhibitors inhibit secretion of wild type α1-AT (20.Gross V. Tran-Thi T.-A. Schwarz R.T. Elbein A.D. Decker K. Heinrich P.C. Biochem. J. 1986; 236: 853-860Crossref PubMed Scopus (36) Google Scholar). Studies of another mutant α1-AT molecule which is retained and degraded in the ER, α1-ATHONG KONG, have shown that glucosidase and mannosidase inhibitors alter ER degradation—accelerated by glucosidase inhibitors and delayed by mannosidase inhibitors (4.Liu Y. Choudhury P. Cabral C.M. Sifers R.N. J. Biol. Chem. 1997; 272: 7946-7951Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, 5.Liu Y. Choudhury P. Cabral C.M. Sifers R.N. J. Biol. Chem. 1999; 274: 5861-5867Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar). However, there are no previous reports of the effect of these inhibitors on mutant α1-ATZ. The results show that there are effects on ER degradation but, to our surprise, several glucosidase and mannosidase inhibitors mediated an increase in secretion of α1-ATZ. Because the mutant α1-ATZ molecule partially retains functional activity (15.Bathurst I.C. Travis J. George P.M. Carrell R.W. FEBS Lett. 1984; 177: 179-183Crossref PubMed Scopus (46) Google Scholar, 16.Ogushi F. Fells G.A. Hubbard R.C. Straus S.D. Crystal R.G. J. Clin. Invest. 1987; 89: 1366-1374Crossref Scopus (159) Google Scholar) and because clinical studies have suggested that only partial correction is needed for prevention of both liver and lung injury in α1-AT deficiency (17.Wu Y. Whitman I. Molmenti E. Moore K. Hippenmeyer P. Perlmutter D.H. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 9014-9018Crossref PubMed Scopus (234) Google Scholar, 21.Campbell E.J. Campbell M.A. Boukedes S.S. Owen C.A. J. Clin. Invest. 1999; 104: 337-344Crossref PubMed Scopus (100) Google Scholar), the effects of this class of drugs are of therapeutic as well as pathobiologic interest. Materials—Neutrophil elastase was obtained from Athens Research and Technology, Inc. (Athens, GA). Kifunensine (KIF), castanospermine (CST), and N-methyldeoxynojirimycin (MDNJ) were obtained from Toronto Research Chemicals (Ontario, Canada).N-butyldeoxynojirimycin (BDNJ) was a generous gift from Dr. G. Jacob (Monsanto, St. Louis, MO). 1,4-Dideoxy-1,4-imino-d-mannitol hydrochloride (DIM) was obtained from Sigma. Deoxymannojirimycin (DMJ) was obtained from Calbiochem. Endoglycosidase H (Endo H) and N-glycosidase F (PNGase F) were obtained from Roche Molecular Biochemicals. The human fibroblast cell line CJZ12B engineered for stable expression of mutant α1-ATZ by transduction of amphotropic recombinant retroviral particles has been previously described (17.Wu Y. Whitman I. Molmenti E. Moore K. Hippenmeyer P. Perlmutter D.H. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 9014-9018Crossref PubMed Scopus (234) Google Scholar). CJZ12B cells were preincubated for 1 h at 37 °C in serum-free DMEM with or without drug. Cells were then subjected to a pulse-chase protocol in the absence or presence of drug. The pulse was 1.5 h using 350–400 fluid and cell were and by as described previously (17.Wu Y. Whitman I. Molmenti E. Moore K. Hippenmeyer P. Perlmutter D.H. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 9014-9018Crossref PubMed Scopus (234) Google Scholar). of were subjected to acid to that there were of of in the absence or presence of drug. The were and on a the that the of CJZ12B cells during the pulse-chase protein was examined at the of a pulse-chase protocol the absence of in the absence or presence of the and cells were to and then with for were by Cell was also by The of Qu et al. (18.Qu D. Teckman J.H. Omura S. Perlmutter D.H. J. Biol. Chem. 1996; 271: 22791-22795Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar) was α1-ATZ was used to the cell with for at The were then by and in a at 37 °C for the indicated were at the indicated and the were on with was using a of in with and were with to and the were in of and were at °C for For H the were with of and of H was using of a 1 For N-glycosidase F the were to of of of N-glycosidase and of were at 37 °C and then in for Cells were subjected to a pulse-chase and the medium was h of the This medium was for at 37 °C with neutrophil in from 1 to in of and then subjected to with for we examined the effect of several glucosidase inhibitors, and on the of α1-ATZ 1 In the absence of α1-ATZ at Previous studies have shown that this a intermediate with oligosaccharide side chains (17.Wu Y. Whitman I. Molmenti E. Moore K. Hippenmeyer P. Perlmutter D.H. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 9014-9018Crossref PubMed Scopus (234) Google Scholar). In the presence of or α1-ATZ more inhibition of glucose we examined the effect of on the fate of α1-ATZ in pulse-chase The results show that in the absence of the α1-ATZ is retained for 1 h to from and with only of the α1-AT in In the presence of the α1-ATZ also from and h of the in this there is a marked increase in the of α1-ATZ secreted into the h into the of the α1-ATZ was secreted into the medium in the presence of as with in the absence of The for of α1-ATZ from were h in the absence and h in the presence of These results that there is secretion of α1-ATZ in the presence of also examined the effect of the glucosidase inhibitor on the fate of α1-ATZ in cells 1 The results also show that the α1-ATZ in the presence of from more but, in to there was no increase in the secretion of α1-ATZ. These results that the effect of on secretion of α1-ATZ is with a glucosidase inhibitor, show that also increase secretion of α1-ATZ It is at this or Previous studies have suggested that there may be in the of the glucosidase inhibition and in the number of glucose residues on the oligosaccharide side chains of wild type α1-AT with and (20.Gross V. Tran-Thi T.-A. Schwarz R.T. Elbein A.D. Decker K. Heinrich P.C. Biochem. J. 1986; 236: 853-860Crossref PubMed Scopus (36) Google Scholar, R.C. 1995; 5: PubMed Scopus Google Scholar). may mediate the secretion of α1-ATZ a effect or an effect that is to glucosidase we examined the effect of on ER degradation of α1-ATZ. is known to the interaction of glycoproteins with calnexin (2.Helenius A. Trombetta E.S. Hebert D.N. Simons J.F. Trends Cell Biol. 1997; 7: 193-200Abstract Full Text PDF PubMed Scopus (345) Google A. Petrescu S.M. Rudd P.M. Dwek R.A. Thomas D.Y. Bergeron J.J.M. Cell. 1997; 88: 29-38Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar). previous studies have indicated that interaction with calnexin at least in required for proteasomal degradation of α1-ATZ and that is the complex which is by the ubiquitin and the proteasome (18.Qu D. Teckman J.H. Omura S. Perlmutter D.H. J. Biol. Chem. 1996; 271: 22791-22795Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar). for in the pulse-chase in cells in 1 that there is no in the of α1-ATZ from in the presence of we to more specifically the effect of on degradation of α1-ATZ using the translocation Previous studies have indicated that α1-ATZ is specifically degraded in this cell by a mechanism which involves the proteasome and which the degradation of α1-ATZ in cells (18.Qu D. Teckman J.H. Omura S. Perlmutter D.H. J. Biol. Chem. 1996; 271: 22791-22795Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar). In the α1-ATZ to and is degraded of the the is preincubated with the α1-ATZ is degraded more and only by of the the is only during the a which with trimming by glucosidase of glycoproteins from calnexin D.N. A. Cell. 1995; Full Text PDF PubMed Scopus Google Scholar), the α1-ATZ is degraded at a which is rather is to that in control with and In from these were and subjected to with to calnexin and This protocol was to α1-ATZ be by to the of and and The results show that α1-ATZ is by in the this complex of the The of of the complex is to of α1-ATZ in that have been subjected to α1-ATZ is by in that were preincubated with α1-ATZ is with control α1-ATZ is with with This complex is at the of the and Previous studies have shown that misfolded may in with glucose trimming is I. A. Biol. Cell. 1997; PubMed Scopus Google Scholar). This that in the presence of there is or interaction of α1-ATZ with calnexin, that a of the α1-ATZ has to and that the complex is or glucose trimming in interaction with calnexin, α1-ATZ is degraded by an pathway that involves an This pathway appears to also the proteasome because is by the proteasomal inhibitors in the cell as well as in CJZ12B cells This mechanism also the inhibition of α1-ATZ degradation in the cell with into in for the in we that only of α1-ATZ is with in the presence of This that one or more additional are involved in degradation of α1-ATZ these studies have indicated that ER mannosidases play a role in the processing of carbohydrate side chains of glycoproteins in the ER (4.Liu Y. Choudhury P. Cabral C.M. Sifers R.N. J. Biol. Chem. 1997; 272: 7946-7951Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, 5.Liu Y. Choudhury P. Cabral C.M. Sifers R.N. J. Biol. Chem. 1999; 274: 5861-5867Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar). we examined the effect of a mannosidase I inhibitor, a mannosidase II inhibitor, and an inhibitor of both mannosidases I and S. Spiro R.G. Biochem. 1996; PubMed Scopus Google Scholar). The effect of these inhibitors on the of α1-ATZ is shown in A. There is in the presence of and in the presence of we examined the effect of these inhibitors on the fate of α1-ATZ in pulse-chase In the presence of and the α1-ATZ is retained for a of than in and there is a marked increase in the of α1-ATZ that appears The α1-ATZ that is secreted in the presence of and is as with the secreted in the presence of In the mannosidase II inhibitor has no effect on degradation or secretion of α1-ATZ is in these as by the that the of α1-ATZ that the fluid has a more at These that and mediate a marked in degradation and an increase in secretion of α1-ATZ. The effect of and on secretion of α1-ATZ involves a mechanism than the effect of because the α1-ATZ that is secreted in of these has a The also ER mannosidase I ER mannosidase II in an important role in the fate of the misfolded α1-ATZ α1-ATZ secreted in the presence of or has or oligosaccharide side we examined the effect of H and F In the wild type α1-AT in the extracellular fluid was to with H to an by F as In CJZ12B cells with the α1-ATZ was partially and partially to H A the of α1-ATZ with The and partially of α1-ATZ with on one or two of its carbohydrate side The α1-ATZ with complex at of its side This was because of because with of H has previously been for the wild type α1-AT secreted by in the presence of (20.Gross V. Tran-Thi T.-A. Schwarz R.T. Elbein A.D. Decker K. Heinrich P.C. Biochem. J. 1986; 236: 853-860Crossref PubMed Scopus (36) Google Scholar). of one, or carbohydrate side chains to the complex type in the presence of is a of the cell expression in of which glycoproteins during inhibition of glucosidases P. Spiro R.G. 1998; PubMed Scopus Google Scholar). In CJZ12B cells with the α1-ATZ was to by F as In CJZ12B cells with the α1-ATZ was to that is an intermediate with carbohydrate side examined the that α1-ATZ secreted in the presence of or form an complex with neutrophil elastase The results show that wild type α1-AT from cells and molecular with elastase to form at of elastase with by of elastase The that have partial during the or during The α1-ATZ. The α1-ATZ secreted from CJZ12B cells also molecular with elastase that to to at of elastase and to the complex form of The α1-ATZ secreted from or CJZ12B also with In this the complex at Because α1-ATZ secreted in the presence of or is the complex to the complex with wild type α1-AT from The α1-ATZ from or CJZ12B cells only to form of elastase is and only at of elastase is to the complex These that α1-ATZ secreted in the presence of or is in is apparently in activity than wild type α1-AT secreted by results have been described for wild type human α1-AT secreted with type carbohydrate side chains by M.-H. 1998; PubMed Scopus Google Scholar, M.-H. 1997; PubMed Scopus Google Scholar). the results of these studies that the glucosidase inhibitor secretion of α1-ATZ and that the mannosidase inhibitors and mediate both degradation and secretion of α1-ATZ. The suggest that there are at least by which in oligosaccharide side chain trimming be and a of misfolded glycoproteins to the secretory In one previous study, has been shown to increase secretion of of I. A. Biol. Cell. 1997; PubMed Scopus Google Scholar), there are no previous reports of a effect for or It is at this the alterations in the of the oligosaccharide side chain the side chain from with responsible for its the side chain to with that facilitate the folding of the mutant α1-ATZ or in alterations in the of α1-ATZ in a that its folding is In the of α1-ATZ in the presence of mannosidase inhibitors and the ERGIC-53 pathway is an for et al. M. Hauri H.-P. Nichols W.C. Ginsburg D. Kaufman R.J. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar) have shown that ERGIC-53 secretion of coagulation factors V and by of mannose oligosaccharide side with the ERGIC-53 pathway an for the in degradation that also in the presence of and previous studies have suggested the that are responsible for of secretory and membrane during with mannosidase inhibitors C.A. Burda P. Roth J. Aebi M. J. Cell Biol. 1998; 142: 1223-1233Crossref PubMed Scopus (303) Google Scholar, 9.Yang M. Omura S. Bonifacino J.S. Weissman A.M. J. Exp. Med. 1998; 187: 835-846Crossref PubMed Scopus (202) Google Scholar). of studies in the (4.Liu Y. Choudhury P. Cabral C.M. Sifers R.N. J. Biol. Chem. 1997; 272: 7946-7951Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, 5.Liu Y. Choudhury P. Cabral C.M. Sifers R.N. J. Biol. Chem. 1999; 274: 5861-5867Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar, 6.Jakob C.A. Burda P. Roth J. Aebi M. J. Cell Biol. 1998; 142: 1223-1233Crossref PubMed Scopus (303) Google Scholar, 7.Kearse K.P. Williams D.B. Singer A. EMBO J. 1994; 13: 3678-3686Crossref PubMed Scopus (111) Google Scholar, 8.Moore S. Spiro R. J. Biol. Chem. 1993; 268: 3809-3813Abstract Full Text PDF PubMed Google Scholar, 9.Yang M. Omura S. Bonifacino J.S. Weissman A.M. J. Exp. Med. 1998; 187: 835-846Crossref PubMed Scopus (202) Google Scholar, 10.Vierhoeven A.J.M. Neve B.P. Jansen H. Biochem. J. 1999; 337: 133-140Crossref PubMed Google Scholar, V. Tran-Thi T.-A. Schwarz R.T. Elbein A.D. Decker K. Heinrich P.C. Biochem. J. 1986; 236: 853-860Crossref PubMed Scopus (36) Google Scholar, 21.Campbell E.J. Campbell M.A. Boukedes S.S. Owen C.A. J. Clin. Invest. 1999; 104: 337-344Crossref PubMed Scopus (100) Google Scholar, R.C. 1995; 5: PubMed Scopus Google Scholar, D.N. A. Cell. 1995; Full Text PDF PubMed Scopus Google Scholar, I. A. Biol. Cell. 1997; PubMed Scopus Google Scholar, S. Spiro R.G. Biochem. 1996; PubMed Scopus Google Scholar) that there are and in the effects of glucosidase and mannosidase inhibitors and that there may also be in their effects on the protein is secretory, wild unassembled, or The results also further evidence that and have and effects on ER degradation and secretion of the misfolded α1-ATZ and acid mediate increases in secretion of α1-ATZ without its degradation J. A. and Perlmutter, D. H. Proc. Natl. Acad. Sci. U. S. in pressGoogle Scholar). and of to °C are associated with a in degradation of α1-ATZ without in secretion J. A. and Perlmutter, D. H. Proc. Natl. Acad. Sci. U. S. in pressGoogle Scholar). and of to °C are associated with degradation and secretion J. A. and Perlmutter, D. H. Proc. Natl. Acad. Sci. U. S. in pressGoogle Scholar). Because the mutant α1-ATZ retains functional activity and because clinical studies have suggested that only partial correction of the secretory is needed for prevention of both liver and lung disease in α1-AT deficiency, which secretion is a for chemoprophylaxis in patients with this deficiency. studies have shown that a is an J. A. and Perlmutter, D. H. Proc. Natl. Acad. Sci. U. S. in pressGoogle Scholar). The current that may be another Indeed, a on is in clinical as an for Struct. Biol. 1995; 5: PubMed Scopus Google Scholar). The mannosidase inhibitors and are also drugs for chemoprophylaxis because degradation of α1-ATZ as well as increase its drugs on these have the to lung injury to increase the of liver injury in α1-AT-deficient are to for this

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