Z突变α_1-抗胰蛋白酶缺乏症的研究进展
|
摘要
α_1-抗胰蛋白酶(α_1-AT)属于丝氨酸蛋白酶抑制剂家族(Serpin),是人血浆中最重要的蛋白酶抑制剂,能抑制多种蛋白酶,从而抑制组织的降解。经典的α_1-AT缺乏症由Z突变(Glu342Lys)引起,该突变导致蛋白在肝细胞内形成多聚体并聚积,引起肝细胞损伤,同时由于血浆中该蛋白浓度的减少,破坏了蛋白酶与蛋白酶抑制剂之间的平衡,故可引起肺气肿和新生儿肝炎等疾病。该文主要从α_1-AT的分子结构、基因多态性,及其相关疾病的治疗等方面概述Z突变所致的α_1-AT缺乏症的致病机制和相关预后的研究进展。
α_1-Antitrypsin(α_1-AT) belongs to serine protease inhibitor(Serpin) superfamily and is the main protease inhibitor in human circulation. It can inhibit many proteases to protect tissues from digradation. The mutant Z(Glu342Lys) of α_1-AT predisposes to the early onset of emphysema due to decreased functional α_1-AT in the lung and to neonatal hepatitis due to accumulation of α_1-AT polymers in the endoplasmic reticulum of hepatocytes, which disrupts the balance between protease and protease inhibitors. This paper reviews recent research progress on the pathogenic mechanism and the prognosis of α_1-antitrypsin deficiency.
α_1-Antitrypsin(α_1-AT) belongs to serine protease inhibitor(Serpin) superfamily and is the main protease inhibitor in human circulation. It can inhibit many proteases to protect tissues from digradation. The mutant Z(Glu342Lys) of α_1-AT predisposes to the early onset of emphysema due to decreased functional α_1-AT in the lung and to neonatal hepatitis due to accumulation of α_1-AT polymers in the endoplasmic reticulum of hepatocytes, which disrupts the balance between protease and protease inhibitors. This paper reviews recent research progress on the pathogenic mechanism and the prognosis of α_1-antitrypsin deficiency.
引文
[1]Lomas DA,Hurst JR,Gooptu B.Update on alpha-1 antitrypsin deficiency:new therapies[J].J Hepatol,2016,65(2):413-424.
[2]徐凌,蔡柏蔷.α1抗胰蛋白酶研究的新进展[J].国际呼吸杂志,2001,21(1):30-32.
[3]Zuo L,Pannell BK,Zhou T,et al.Historical role of alpha-1-antitrypsin deficiency in respiratory and hepatic complications[J].Gene,2016,589(2):118-122.
[4]Hughes VA,Meklemburg R,Bottomley SP,et al.The Z mutation alters the global structural dynamics ofα1-antitrypsin[J].PLo S One,2014,9(9):e102617.
[5]Flotte TR,Mueller C.Gene therapy for alpha-1 antitrypsin deficiency[J].Hum Mol Genet,2011,20(R1):R87-R92.
[6]Duvoix A,Roussel BD,Lomas DA.Molecular pathogenesis of alpha-1-antitrypsin deficiency[J].Rev Mal Respir,2014,31(10):992-1002.
[7]Huang X,Zheng Y,Zhang F,et al.Molecular mechanism of Zα1-antitrypsin deficiency[J].J Biol Chem,2016,291(30):15674-15686.
[8]Tucker HM,Mottonen J,Goldsmith EJ,et al.Engineering of plasminogen activator inhibitor-1 to reduce the rate of latency transition[J].Nat Struct Biol,1995,2(6):442-445.
[9]Bashir A,Shah NN,Hazari YM,et al.Novel variants of SERPIN1A gene:interplay between alpha1-antitrypsin deficiency and chronic obstructive pulmonary disease[J].Respir Med,2016,117:139-149.
[10]Hatipo?lu U,Stoller JK.α1-Antitrypsin deficiency[J].Clin Chest Med,2016,37(3):487-504.
[11]Zorzetto M,Ferrarotti I,Campo I,et al.Identification of a novel alpha1-antitrypsin null variant(Q0Cairo)[J].Diagn Mol Pathol,2005,14(2):121-124.
[12]Gooptu B,Dickens JA,Lomas DA.The molecular and cellular pathology ofα1-antitrypsin deficiency[J].Trends Mol Med,2014,20(2):116-127.
[13]Salahuddin P.Genetic variants ofα1-antitrypsin[J].Curr Protein Pept Sci,2010,11(2):101-117.
[14]Fra A,Cosmi F,Ordo?ez A,et al.Polymers of Zα1-antitrypsin are secreted in cell models of disease[J].Eur Respir J,2016,47(3):1005-1009.
[15]Knaupp AS,Levina V,Robertson AL,et al.Kinetic instability of the serpin Zα1-antitrypsin promotes aggregation[J].J Mol Biol,2010,396(2):375-383.
[16]Lomas DA,Evans DL,Finch JT,et al.The mechanism of Z alpha 1-antitrypsin accumulation in the liver[J].Nature,1992,357(6379):605-607.
[17]Davis RL,Shrimpton AE,Holohan PD,et al.Familial dementia caused by polymerization of mutant neuroserpin[J].Nature,1999,401(6751):376-379.
[18]Yamasaki M,Li W,Johnson DJ,et al.Crystal structure of a stable dimer reveals the molecular basis of serpin polymerization[J].Nature,2008,455(7217):1255-1258.
[19]Yamasaki M,Sendall TJ,Pearce MC,et al.Molecular basis ofα1-antitrypsin deficiency revealed by the structure of a domain-swapped trimer[J].EMBORep,2011,12(10):1011-1017.
[20]Bottomley SP.The structural diversity inα1-antitrypsin misfolding[J].EMBORep,2011,12(10):983-984.
[21]Dolmer K,Gettins PG.How the serpinα1-proteinase inhibitor folds[J].J Biol Chem,2012,287(15):12425-12432.
[22]Marciniuk DD,Hernandez P,Balter M,et al.Alpha-1 antitrypsin deficiency targeted testing and augmentation therapy:a Canadian Thoracic Society clinical practice guideline[J].Can Respir J,2012,19(2):109-116.
[23]Dickens JA,Lomas DA.Why has it been so difficult to prove the efficacy of alpha-1-antitrypsin replacement therapy?Insights from the study of disease pathogenesis[J].Drug Des Devel Ther,2011,5:391-405.
[24]Lockett AD,Van Demark M,Gu Y,et al.Effect of cigarette smoke exposure and structural modifications on theα-1 antitrypsin interaction with caspases[J].Mol Med,2012,18:445-454.
[25]Alam S,Li Z,Janciauskiene S,et al.Oxidation of Zα1-antitrypsin by cigarette smoke induces polymerization:a novel mechanism of early-onset emphysema[J].Am J Respir Cell Mol Biol,2011,45(2):261-269.
[26]Sandhaus RA.α1-Antitrypsin deficiency·6:new and emerging treatments forα1-antitrypsin deficiency[J].Thorax,2004,59(10):904-909.
[27]Ferrarotti I,Thun GA,Zorzetto M,et al.Serum levels and genotype distribution ofα1-antitrypsin in the general population[J].Thorax,2012,67(8):669-674.
[28]Teschler H.Long-term experience in the treatment ofα1-antitrypsin deficiency:25 years of augmentation therapy[J].Eur Respir Rev,2015,24(135):46-51.
[29]Stolk J,Stockley RA,Stoel BC,et al.Randomised controlled trial for emphysema with a selective agonist of theγ-type retinoic acid receptor[J].Eur Respir J,2012,40(2):306-312.
[30]Zuo L,Pannell BK,Re AT,et al.PO2 cycling protects diaphragm function during reoxygenation via ROS,Akt,ERK,and mitochondrial channels[J].Am JPhysiol Cell Physiol,2015,309(11):C759-C766.
[31]Stoller JK,Aboussouan LS,Kanner RE,et al.Characteristics ofα-1 antitrypsindeficient individuals in the long-term oxygen treatment trial and comparison with other subjects with chronic obstructive pulmonary disease[J].Ann Am Thorac Soc,2015,12(12):1796-1804.
[32]Teckman JH,Jain A.Advances in alpha-1-antitrypsin deficiency liver disease[J].Curr Gastroenterol Rep,2014,16(1):1-7.
[33]Lomas DA.Twenty years of polymers:a personal perspective on alpha-1antitrypsin deficiency[J].COPD,2013,10(Suppl 1):17-25.
[34]Nyon MP,Prentice T,Day J,et al.An integrative approach combining ion mobility mass spectrometry,X-ray crystallography,and nuclear magnetic resonance spectroscopy to study the conformational dynamics ofα1-antitrypsin upon ligand binding[J].Protein Sci,2015,24(8):1301-1312.
[35]Ordó?ez A,Pérez J,Tan L,et al.A single-chain variable fragment intrabody prevents intracellular polymerization of Zα1-antitrypsin while allowing its antiproteinase activity[J].FASEB J,2015,29(6):2667-2678.
[36]Teckman JH.Lack of effect of oral 4-phenylbutyrate on serum alpha-1-antitrypsin in patients with alpha-1-antitrypsin deficiency:a preliminary study[J].J Pediatr Gastroenterol Nutr,2004,39(1):34-37.
[37]Wang Y,Perlmutter DH.Targeting intracellular degradation pathways for treatment of liver disease caused byα1-antitrypsin deficiency[J].Pediatr Res,2014,75(1-2):133-139.
[38]Tang Y,Fickert P,Trauner M,et al.Autophagy induced by exogenous bile acids is therapeutic in a model ofα-1-AT deficiency liver disease[J].Am JPhysiol Gastrointest Liver Physiol,2016,311(1):G156-G165.
[39]Yusa K,Rashid ST,Strick-Marchand H,et al.Targeted gene correction ofα1-antitrypsin deficiency in induced pluripotent stem cells[J].Nature,2011,478(7369):391-394.
[2]徐凌,蔡柏蔷.α1抗胰蛋白酶研究的新进展[J].国际呼吸杂志,2001,21(1):30-32.
[3]Zuo L,Pannell BK,Zhou T,et al.Historical role of alpha-1-antitrypsin deficiency in respiratory and hepatic complications[J].Gene,2016,589(2):118-122.
[4]Hughes VA,Meklemburg R,Bottomley SP,et al.The Z mutation alters the global structural dynamics ofα1-antitrypsin[J].PLo S One,2014,9(9):e102617.
[5]Flotte TR,Mueller C.Gene therapy for alpha-1 antitrypsin deficiency[J].Hum Mol Genet,2011,20(R1):R87-R92.
[6]Duvoix A,Roussel BD,Lomas DA.Molecular pathogenesis of alpha-1-antitrypsin deficiency[J].Rev Mal Respir,2014,31(10):992-1002.
[7]Huang X,Zheng Y,Zhang F,et al.Molecular mechanism of Zα1-antitrypsin deficiency[J].J Biol Chem,2016,291(30):15674-15686.
[8]Tucker HM,Mottonen J,Goldsmith EJ,et al.Engineering of plasminogen activator inhibitor-1 to reduce the rate of latency transition[J].Nat Struct Biol,1995,2(6):442-445.
[9]Bashir A,Shah NN,Hazari YM,et al.Novel variants of SERPIN1A gene:interplay between alpha1-antitrypsin deficiency and chronic obstructive pulmonary disease[J].Respir Med,2016,117:139-149.
[10]Hatipo?lu U,Stoller JK.α1-Antitrypsin deficiency[J].Clin Chest Med,2016,37(3):487-504.
[11]Zorzetto M,Ferrarotti I,Campo I,et al.Identification of a novel alpha1-antitrypsin null variant(Q0Cairo)[J].Diagn Mol Pathol,2005,14(2):121-124.
[12]Gooptu B,Dickens JA,Lomas DA.The molecular and cellular pathology ofα1-antitrypsin deficiency[J].Trends Mol Med,2014,20(2):116-127.
[13]Salahuddin P.Genetic variants ofα1-antitrypsin[J].Curr Protein Pept Sci,2010,11(2):101-117.
[14]Fra A,Cosmi F,Ordo?ez A,et al.Polymers of Zα1-antitrypsin are secreted in cell models of disease[J].Eur Respir J,2016,47(3):1005-1009.
[15]Knaupp AS,Levina V,Robertson AL,et al.Kinetic instability of the serpin Zα1-antitrypsin promotes aggregation[J].J Mol Biol,2010,396(2):375-383.
[16]Lomas DA,Evans DL,Finch JT,et al.The mechanism of Z alpha 1-antitrypsin accumulation in the liver[J].Nature,1992,357(6379):605-607.
[17]Davis RL,Shrimpton AE,Holohan PD,et al.Familial dementia caused by polymerization of mutant neuroserpin[J].Nature,1999,401(6751):376-379.
[18]Yamasaki M,Li W,Johnson DJ,et al.Crystal structure of a stable dimer reveals the molecular basis of serpin polymerization[J].Nature,2008,455(7217):1255-1258.
[19]Yamasaki M,Sendall TJ,Pearce MC,et al.Molecular basis ofα1-antitrypsin deficiency revealed by the structure of a domain-swapped trimer[J].EMBORep,2011,12(10):1011-1017.
[20]Bottomley SP.The structural diversity inα1-antitrypsin misfolding[J].EMBORep,2011,12(10):983-984.
[21]Dolmer K,Gettins PG.How the serpinα1-proteinase inhibitor folds[J].J Biol Chem,2012,287(15):12425-12432.
[22]Marciniuk DD,Hernandez P,Balter M,et al.Alpha-1 antitrypsin deficiency targeted testing and augmentation therapy:a Canadian Thoracic Society clinical practice guideline[J].Can Respir J,2012,19(2):109-116.
[23]Dickens JA,Lomas DA.Why has it been so difficult to prove the efficacy of alpha-1-antitrypsin replacement therapy?Insights from the study of disease pathogenesis[J].Drug Des Devel Ther,2011,5:391-405.
[24]Lockett AD,Van Demark M,Gu Y,et al.Effect of cigarette smoke exposure and structural modifications on theα-1 antitrypsin interaction with caspases[J].Mol Med,2012,18:445-454.
[25]Alam S,Li Z,Janciauskiene S,et al.Oxidation of Zα1-antitrypsin by cigarette smoke induces polymerization:a novel mechanism of early-onset emphysema[J].Am J Respir Cell Mol Biol,2011,45(2):261-269.
[26]Sandhaus RA.α1-Antitrypsin deficiency·6:new and emerging treatments forα1-antitrypsin deficiency[J].Thorax,2004,59(10):904-909.
[27]Ferrarotti I,Thun GA,Zorzetto M,et al.Serum levels and genotype distribution ofα1-antitrypsin in the general population[J].Thorax,2012,67(8):669-674.
[28]Teschler H.Long-term experience in the treatment ofα1-antitrypsin deficiency:25 years of augmentation therapy[J].Eur Respir Rev,2015,24(135):46-51.
[29]Stolk J,Stockley RA,Stoel BC,et al.Randomised controlled trial for emphysema with a selective agonist of theγ-type retinoic acid receptor[J].Eur Respir J,2012,40(2):306-312.
[30]Zuo L,Pannell BK,Re AT,et al.PO2 cycling protects diaphragm function during reoxygenation via ROS,Akt,ERK,and mitochondrial channels[J].Am JPhysiol Cell Physiol,2015,309(11):C759-C766.
[31]Stoller JK,Aboussouan LS,Kanner RE,et al.Characteristics ofα-1 antitrypsindeficient individuals in the long-term oxygen treatment trial and comparison with other subjects with chronic obstructive pulmonary disease[J].Ann Am Thorac Soc,2015,12(12):1796-1804.
[32]Teckman JH,Jain A.Advances in alpha-1-antitrypsin deficiency liver disease[J].Curr Gastroenterol Rep,2014,16(1):1-7.
[33]Lomas DA.Twenty years of polymers:a personal perspective on alpha-1antitrypsin deficiency[J].COPD,2013,10(Suppl 1):17-25.
[34]Nyon MP,Prentice T,Day J,et al.An integrative approach combining ion mobility mass spectrometry,X-ray crystallography,and nuclear magnetic resonance spectroscopy to study the conformational dynamics ofα1-antitrypsin upon ligand binding[J].Protein Sci,2015,24(8):1301-1312.
[35]Ordó?ez A,Pérez J,Tan L,et al.A single-chain variable fragment intrabody prevents intracellular polymerization of Zα1-antitrypsin while allowing its antiproteinase activity[J].FASEB J,2015,29(6):2667-2678.
[36]Teckman JH.Lack of effect of oral 4-phenylbutyrate on serum alpha-1-antitrypsin in patients with alpha-1-antitrypsin deficiency:a preliminary study[J].J Pediatr Gastroenterol Nutr,2004,39(1):34-37.
[37]Wang Y,Perlmutter DH.Targeting intracellular degradation pathways for treatment of liver disease caused byα1-antitrypsin deficiency[J].Pediatr Res,2014,75(1-2):133-139.
[38]Tang Y,Fickert P,Trauner M,et al.Autophagy induced by exogenous bile acids is therapeutic in a model ofα-1-AT deficiency liver disease[J].Am JPhysiol Gastrointest Liver Physiol,2016,311(1):G156-G165.
[39]Yusa K,Rashid ST,Strick-Marchand H,et al.Targeted gene correction ofα1-antitrypsin deficiency in induced pluripotent stem cells[J].Nature,2011,478(7369):391-394.