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Protein & Peptide Letters

Editor-in-Chief

ISSN (Print): 0929-8665
ISSN (Online): 1875-5305

Letter Article

Antioxidant Responses are Crucial for Defense against Misfolded Human Z-Type α1-Antitrypsin

Author(s): Hana Im* and Jaeyeon Lim

Volume 29, Issue 5, 2022

Published on: 22 April, 2022

Page: [384 - 391] Pages: 8

DOI: 10.2174/0929866529666220321151913

Price: $65

Abstract

Background: The Z-type variant of human α1-antitrypsin is involved in liver cirrhosis and pulmonary emphysema. Due to its slow folding characteristics, this variant accumulates folding intermediates and forms protein aggregates within hepatocytes. Misfolded proteins may induce oxidative stress and subsequent cell death.

Objective: The potential application of antioxidant response signaling pathway and antioxidants to cope with Z-type α1-antitrypsin-induced oxidative stress was evaluated.

Methods: Overexpression of Z-type α1-antitrypsin in Saccharomyces cerevisiae provoked oxidative stress and increased susceptibility to oxidative challenges such as hydrogen peroxide treatment. Deletion of antioxidant-response genes, including yap1, skn7, sod2, tsa1, and pst2, exacerbated the slow growth phenotype of Z-type α1-antitrypsin-expressing cells. Antioxidant treatment alleviated oxidative stress and cytotoxicity induced by Z-type α1-antitrypsin.

Results: Our results show that cellular antioxidant capacity is crucial to protection against misfolded Z-type α1-antitrypsin.

Conclusion: The information obtained here may be used to prevent oxidative stress caused by misfolded proteins, which are associated with several degenerative diseases, including amyotrophic lateral sclerosis and Parkinson’s disease.

Keywords: α1-Antitrypsin, antioxidant, antitrypsin variant, misfolded protein, protein folding, oxidative stress.

Graphical Abstract
[1]
Carrell, R.W.; Jeppsson, J-O.; Laurell, C-B.; Brennan, S.O.; Owen, M.C.; Vaughan, L.; Boswell, D.R. Structure and variation of human α 1-antitrypsin. Nature, 1982, 298(5872), 329-334.
[http://dx.doi.org/10.1038/298329a0] [PMID: 7045697]
[2]
Creighton, T.E. Protein folding. Up the kinetic pathway. Nature, 1992, 356(6366), 194-195.
[http://dx.doi.org/10.1038/356194a0] [PMID: 1552936]
[3]
Giacopuzzi, E.; Laffranchi, M.; Berardelli, R.; Ravasio, V.; Ferrarotti, I.; Gooptu, B.; Borsani, G.; Fra, A. Real-world clinical applicability of pathogenicity predictors assessed on SERPINA1 mutations in alpha-1-antitrypsin deficiency. Hum. Mutat., 2018, 39(9), 1203-1213.
[http://dx.doi.org/10.1002/humu.23562] [PMID: 29882371]
[4]
Stein, P.E.; Carrell, R.W. What do dysfunctional serpins tell us about molecular mobility and disease? Nat. Struct. Biol., 1995, 2(2), 96-113.
[http://dx.doi.org/10.1038/nsb0295-96] [PMID: 7749926]
[5]
Perlmutter, D.H. Liver injury in α1-antitrypsin deficiency: An aggregated protein induces mitochondrial injury. J. Clin. Invest., 2002, 110(11), 1579-1583.
[http://dx.doi.org/10.1172/JCI0216787] [PMID: 12464659]
[6]
Eriksson, S.; Carlson, J.; Velez, R. Risk of cirrhosis and primary liver cancer in α 1-antitrypsin deficiency. N. Engl. J. Med., 1986, 314(12), 736-739.
[http://dx.doi.org/10.1056/NEJM198603203141202] [PMID: 3485248]
[7]
Yu, M-H.; Lee, K.N.; Kim, J. The Z type variation of human α 1-antitrypsin causes a protein folding defect. Nat. Struct. Biol., 1995, 2(5), 363-367.
[http://dx.doi.org/10.1038/nsb0595-363] [PMID: 7664092]
[8]
Mahadeva, R.; Chang, W.S.; Dafforn, T.R.; Oakley, D.J.; Foreman, R.C.; Calvin, J.; Wight, D.G.; Lomas, D.A. Heteropolymerization of S, I, and Z α1-antitrypsin and liver cirrhosis. J. Clin. Invest., 1999, 103(7), 999-1006.
[http://dx.doi.org/10.1172/JCI4874] [PMID: 10194472]
[9]
Singh, A.; Kukreti, R.; Saso, L.; Kukreti, S. Oxidative stress: A key modulator in neurodegenerative diseases. Molecules, 2019, 24(8), 1583.
[http://dx.doi.org/10.3390/molecules24081583] [PMID: 31013638]
[10]
Barnham, K.J.; Masters, C.L.; Bush, A.I. Neurodegenerative diseases and oxidative stress. Nat. Rev. Drug Discov., 2004, 3(3), 205-214.
[http://dx.doi.org/10.1038/nrd1330] [PMID: 15031734]
[11]
Ikawa, M.; Okazawa, H.; Tsujikawa, T.; Matsunaga, A.; Yamamura, O.; Mori, T.; Hamano, T.; Kiyono, Y.; Nakamoto, Y.; Yoneda, M. Increased oxidative stress is related to disease severity in the ALS motor cortex: A PET study. Neurology, 2015, 84(20), 2033-2039.
[http://dx.doi.org/10.1212/WNL.0000000000001588] [PMID: 25904686]
[12]
Basso, M.; Samengo, G.; Nardo, G.; Massignan, T.; D’Alessandro, G.; Tartari, S.; Cantoni, L.; Marino, M.; Cheroni, C.; De Biasi, S.; Giordana, M.T.; Strong, M.J.; Estevez, A.G.; Salmona, M.; Bendotti, C.; Bonetto, V. Characterization of detergent-insoluble proteins in ALS indicates a causal link between nitrative stress and aggregation in pathogenesis. PLoS One, 2009, 4(12), e8130.
[http://dx.doi.org/10.1371/journal.pone.0008130] [PMID: 19956584]
[13]
Tu, B.P.; Weissman, J.S. Oxidative protein folding in eukaryotes: Mechanisms and consequences. J. Cell Biol., 2004, 164(3), 341-346.
[http://dx.doi.org/10.1083/jcb.200311055] [PMID: 14757749]
[14]
Lüth, H.J.; Holzer, M.; Gärtner, U.; Staufenbiel, M.; Arendt, T. Expression of endothelial and inducible NOS-isoforms is increased in Alzheimer’s disease, in APP23 transgenic mice and after experimental brain lesion in rat: Evidence for an induction by amyloid pathology. Brain Res., 2001, 913(1), 57-67.
[http://dx.doi.org/10.1016/S0006-8993(01)02758-5] [PMID: 11532247]
[15]
Malhotra, J.D.; Miao, H.; Zhang, K.; Wolfson, A.; Pennathur, S.; Pipe, S.W.; Kaufman, R.J. Antioxidants reduce endoplasmic reticulum stress and improve protein secretion. Proc. Natl. Acad. Sci. USA, 2008, 105(47), 18525-18530.
[http://dx.doi.org/10.1073/pnas.0809677105] [PMID: 19011102]
[16]
Papp, E.; Száraz, P.; Korcsmáros, T.; Csermely, P. Changes of endoplasmic reticulum chaperone complexes, redox state, and impaired protein disulfide reductase activity in misfolding α1-antitrypsin transgenic mice. FASEB J., 2006, 20(7), 1018-1020.
[http://dx.doi.org/10.1096/fj.05-5065fje] [PMID: 16571774]
[17]
Tenreiro, S.; Outeiro, T.F. Simple is good: Yeast models of neurodegeneration. FEMS Yeast Res., 2010, 10(8), 970-979.
[http://dx.doi.org/10.1111/j.1567-1364.2010.00649.x] [PMID: 20579105]
[18]
Jung, C-H.; Kim, Y-H.; Lee, K. Im, H. Retarded protein folding of the human Z-type α1-antitrypsin variant is suppressed by Cpr2p. Biochem. Biophys. Res. Commun., 2014, 445(1), 191-195.
[http://dx.doi.org/10.1016/j.bbrc.2014.01.156] [PMID: 24502947]
[19]
Adams, A.; Gottschling, D.E.; Kaiser, C.A.; Stearns, T. Techniques and protocols: High-efficiency transformation of yeast.Methods in Yeast Genetics; Dickerson, M.M., Ed.; Cold Spring Harbor Press: Cold Spring Harbor, N.Y., 1997, pp. 99-102.
[20]
Wang, H.; Joseph, J.A. Quantifying cellular oxidative stress by dichlorofluorescein assay using microplate reader. Free Radic. Biol. Med., 1999, 27(5-6), 612-616.
[http://dx.doi.org/10.1016/S0891-5849(99)00107-0] [PMID: 10490282]
[21]
Morgan, B.A.; Banks, G.R.; Toone, W.M.; Raitt, D.; Kuge, S.; Johnston, L.H. The Skn7 response regulator controls gene expression in the oxidative stress response of the budding yeast Saccharomyces cerevisiae. EMBO J., 1997, 16(5), 1035-1044.
[http://dx.doi.org/10.1093/emboj/16.5.1035] [PMID: 9118942]
[22]
Kuge, S.; Jones, N.; Nomoto, A. Regulation of yAP-1 nuclear localization in response to oxidative stress. EMBO J., 1997, 16(7), 1710-1720.
[http://dx.doi.org/10.1093/emboj/16.7.1710] [PMID: 9130715]
[23]
Lee, J.; Godon, C.; Lagniel, G.; Spector, D.; Garin, J.; Labarre, J.; Toledano, M.B. Yap1 and Skn7 control two specialized oxidative stress response regulons in yeast. J. Biol. Chem., 1999, 274(23), 16040-16046.
[http://dx.doi.org/10.1074/jbc.274.23.16040] [PMID: 10347154]
[24]
Marcus, N.Y.; Blomenkamp, K.; Ahmad, M.; Teckman, J.H. Oxidative stress contributes to liver damage in a murine model of alpha-1-antitrypsin deficiency. Exp. Biol. Med. (Maywood), 2012, 237(10), 1163-1172.
[http://dx.doi.org/10.1258/ebm.2012.012106] [PMID: 23104507]
[25]
van Dam, L.; Dansen, T.B. Cross-talk between redox signalling and protein aggregation. Biochem. Soc. Trans., 2020, 48(2), 379-397.
[http://dx.doi.org/10.1042/BST20190054] [PMID: 32311028]
[26]
Haynes, C.M.; Titus, E.A.; Cooper, A.A. Degradation of misfolded proteins prevents ER-derived oxidative stress and cell death. Mol. Cell, 2004, 15(5), 767-776.
[http://dx.doi.org/10.1016/j.molcel.2004.08.025] [PMID: 15350220]
[27]
Cuozzo, J.W.; Kaiser, C.A. Competition between glutathione and protein thiols for disulphide-bond formation. Nat. Cell Biol., 1999, 1(3), 130-135.
[http://dx.doi.org/10.1038/11047] [PMID: 10559898]
[28]
Milhavet, O.; McMahon, H.E.; Rachidi, W.; Nishida, N.; Katamine, S.; Mangé, A.; Arlotto, M.; Casanova, D.; Riondel, J.; Favier, A.; Lehmann, S. Prion infection impairs the cellular response to oxidative stress. Proc. Natl. Acad. Sci. USA, 2000, 97(25), 13937-13942.
[http://dx.doi.org/10.1073/pnas.250289197] [PMID: 11095725]
[29]
Deniaud, A. Sharaf el dein, O.; Maillier, E.; Poncet, D.; Kroemer, G.; Lemaire, C.; Brenner, C. Endoplasmic reticulum stress induces calcium-dependent permeability transition, mitochondrial outer membrane permeabilization and apoptosis. Oncogene, 2008, 27(3), 285-299.
[http://dx.doi.org/10.1038/sj.onc.1210638] [PMID: 17700538]
[30]
Teckman, J.H.; An, J.K.; Blomenkamp, K.; Schmidt, B.; Perlmutter, D. Mitochondrial autophagy and injury in the liver in alpha 1-antitrypsin deficiency. Am. J. Physiol. Gastrointest. Liver Physiol., 2004, 286(5), G851-G862.
[http://dx.doi.org/10.1152/ajpgi.00175.2003] [PMID: 14684378]
[31]
Vargas, M.R.; Johnson, D.A.; Sirkis, D.W.; Messing, A.; Johnson, J.A. Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyotrophic lateral sclerosis. J. Neurosci., 2008, 28(50), 13574-13581.
[http://dx.doi.org/10.1523/JNEUROSCI.4099-08.2008] [PMID: 19074031]
[32]
Kuge, S.; Jones, N. YAP1 dependent activation of TRX2 is essential for the response of Saccharomyces cerevisiae to oxidative stress by hydroperoxides. EMBO J., 1994, 13(3), 655-664.
[http://dx.doi.org/10.1002/j.1460-2075.1994.tb06304.x] [PMID: 8313910]
[33]
Brombacher, K.; Fischer, B.B.; Rüfenacht, K.; Eggen, R.I.L. The role of Yap1p and Skn7p-mediated oxidative stress response in the defence of Saccharomyces cerevisiae against singlet oxygen. Yeast, 2006, 23(10), 741-750.
[http://dx.doi.org/10.1002/yea.1392] [PMID: 16862604]
[34]
Thorpe, G.W.; Fong, C.S.; Alic, N.; Higgins, V.J.; Dawes, I.W. Cells have distinct mechanisms to maintain protection against different reactive oxygen species: Oxidative-stress-response genes. Proc. Natl. Acad. Sci. USA, 2004, 101(17), 6564-6569.
[http://dx.doi.org/10.1073/pnas.0305888101] [PMID: 15087496]
[35]
Krems, B.; Charizanis, C.; Entian, K.D. Mutants of Saccharomyces cerevisiae sensitive to oxidative and osmotic stress. Curr. Genet., 1995, 27(5), 427-434.
[http://dx.doi.org/10.1007/BF00311211] [PMID: 7586028]
[36]
Harrison, F.E.; Allard, J.; Bixler, R.; Usoh, C.; Li, L.; May, J.M.; McDonald, M.P. Antioxidants and cognitive training interact to affect oxidative stress and memory in APP/PSEN1 mice. Nutr. Neurosci., 2009, 12(5), 203-218.
[http://dx.doi.org/10.1179/147683009X423364] [PMID: 19761651]
[37]
Holmay, M.J.; Terpstra, M.; Coles, L.D.; Mishra, U.; Ahlskog, M.; Öz, G.; Cloyd, J.C.; Tuite, P.J. N-Acetylcysteine boosts brain and blood glutathione in Gaucher and Parkinson diseases. Clin. Neuropharmacol., 2013, 36(4), 103-106.
[http://dx.doi.org/10.1097/WNF.0b013e31829ae713] [PMID: 23860343]
[38]
Niedzielska, E.; Smaga, I.; Gawlik, M.; Moniczewski, A.; Stankowicz, P.; Pera, J.; Filip, M. Oxidative stress in neurodegenerative diseases. Mol. Neurobiol., 2016, 53(6), 4094-4125.
[http://dx.doi.org/10.1007/s12035-015-9337-5] [PMID: 26198567]
[39]
Feng, Z.; Qin, C.; Chang, Y.; Zhang, J.T. Early melatonin supplementation alleviates oxidative stress in a transgenic mouse model of Alzheimer’s disease. Free Radic. Biol. Med., 2006, 40(1), 101-109.
[http://dx.doi.org/10.1016/j.freeradbiomed.2005.08.014] [PMID: 16337883]
[40]
Festjens, N.; Kalai, M.; Smet, J.; Meeus, A.; Van Coster, R.; Saelens, X.; Vandenabeele, P. Butylated hydroxyanisole is more than a reactive oxygen species scavenger. Cell Death Differ., 2006, 13(1), 166-169.
[http://dx.doi.org/10.1038/sj.cdd.4401746] [PMID: 16138110]
[41]
Eftekhari, A.; Dizaj, S.M.; Chodari, L.; Sunar, S.; Hasanzadeh, A.; Ahmadian, E.; Hasanzadeh, M. The promising future of nano-antioxidant therapy against environmental pollutants induced-toxicities. Biomed. Pharmacother., 2018, 103, 1018-1027.
[http://dx.doi.org/10.1016/j.biopha.2018.04.126] [PMID: 29710659]
[42]
Ahmadian, E.; Eftekhari, A.; Kavetskyy, T.; Khosroushahi, A.Y.; Turksoy, V.A.; Khalilov, R. Effects of quercetin loaded nanostructured lipid carriers on the paraquat-induced toxicity in human lymphocytes. Pestic. Biochem. Physiol., 2020, 167, 104586.
[http://dx.doi.org/10.1016/j.pestbp.2020.104586] [PMID: 32527420]
[43]
Dodson, M.; de la Vega, M.R.; Cholanians, A.B.; Schmidlin, C.J.; Chapman, E.; Zhang, D.D. Modulating NRF2 in disease: Timing is everything. Annu. Rev. Pharmacol. Toxicol., 2019, 59(1), 555-575.
[http://dx.doi.org/10.1146/annurev-pharmtox-010818-021856] [PMID: 30256716]
[44]
Stephen, D.W.; Rivers, S.L.; Jamieson, D.J. The role of the YAP1 and YAP2 genes in the regulation of the adaptive oxidative stress responses of Saccharomyces cerevisiae. Mol. Microbiol., 1995, 16(3), 415-423.
[http://dx.doi.org/10.1111/j.1365-2958.1995.tb02407.x] [PMID: 7565103]
[45]
Jung, C-H.; Lim, J.H.; Lee, K. Im, H. An endoplasmic reticulum cyclophilin Cpr5p rescues Z-type α1-antitrypsin from retarded folding. Bull. Korean Chem. Soc., 2014, 35(9), 2781-2786.
[http://dx.doi.org/10.5012/bkcs.2014.35.9.2781]
[46]
Lim, J.; Lee, K.; Im, H. Reinforcement of the unfolded protein response mitigates cytotoxicity induced by human Z-type α1-antitrypsin. Bull. Korean Chem. Soc., 2021, 42(6), 900-906.
[http://dx.doi.org/10.1002/bkcs.12289]

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