The molecular and cellular pathology of α1-antitrypsin deficiency

doi:10.1016/j.molmed.2013.10.007

Trends in Molecular Medicine

Volume 20, Issue 2, February 2014, Pages 116-127

https://doi.org/10.1016/j.molmed.2013.10.007 Get rights and content

Highlights

•
Focused overview of 50 years of research into α₁-antitrypsin deficiency.
•
α₁-Antitrypsin misfolding and polymerisation as key events in pathogenesis.
•
Ameliorative versus maladaptive cellular responses to aberrant conformational behaviour.
•
Inherent potential for polymer heterogeneity suggests an evolutionary mechanism.

Since its discovery 50 years ago, α₁-antitrypsin deficiency has represented a case study in molecular medicine, with careful clinical characterisation guiding genetic, biochemical, biophysical, structural, cellular, and in vivo studies. Here we highlight the milestones in understanding the disease mechanisms and show how they have spurred the development of novel therapeutic strategies. α₁-Antitrypsin deficiency is an archetypal conformational disease. Its pathogenesis demonstrates the interplay between protein folding and quality control mechanisms, with aberrant conformational changes causing liver and lung disease through combined loss- and toxic gain-of-function effects. Moreover, α₁-antitrypsin exemplifies the ability of diverse proteins to self-associate into a range of morphologically distinct polymers, suggesting a mechanism for protein and cell evolution.

Section snippets

From syndromics to mechanism: a half-century of characterisation

α₁-Antitrypsin deficiency refers to a syndrome that may be characterised not only by a deficiency of circulating α₁-antitrypsin but also by liver disease and/or emphysema. It was first identified, and an association with lung disease noted, by Laurell and Eriksson 50 years ago [1], and thus the history of its mechanistic elucidation and development of therapeutic strategies reflects that of molecular medicine (Box 1). The field has progressed from first defining the syndrome, using novel

Physiological production and function of α₁-antitrypsin

α₁-Antitrypsin is a 394-residue, 52-kDa glycoprotein that is predominantly synthesised by hepatocytes, but is also produced by lung and gut epithelial cells 17, 18, 19, neutrophils [20], and alveolar macrophages [21]. It is expressed with a secretion signal and is therefore targeted to the ER for folding and glycosylation before export and secretion. It is the major circulating antiprotease but its key function is regulation of the proteolytic effects of neutrophil elastase within the lung. α₁

Polymerisation: the central feature of α₁-antitrypsin deficiency

Z α₁-antitrypsin is retained as ordered polymers that become sequestered in characteristic inclusions within the ER of hepatocytes (monomeric species have also been observed in these inclusions). They are periodic acid–Schiff (PAS)-positive and diastase-resistant [27]. The monomer–polymer transition greatly increases the stability of α₁-antitrypsin. Such hyperstabilisation is also seen during formation of the serpin–enzyme complex (Figure 2) and other conformational transitions in which the

Quality control, ER-associated degradation, and the unfolded protein response

Approximately 70% of the common, severe Z α₁-antitrypsin is degraded within hepatocytes by ER-associated degradation (ERAD), 15% folds effectively and is secreted, whereas the remainder self-associates to form polymers [38]. These are in part degraded by autophagy, but a proportion persists in inclusions 38, 39, 40. Misfolded proteins within the ER lumen usually trigger adaptive measures termed the unfolded protein response (UPR). Indeed, terminally misfolded truncated variants of α₁

Current treatment approaches

The mainstay of treatment for α₁-antitrypsin deficiency-associated liver disease is supportive, with liver transplantation an option for end-stage disease. Emphysema in α₁-antitrypsin-deficient individuals is treated with inhaled bronchodilators and steroids and oxygen when required; smoking cessation is key to slowing the progression of disease [61]. α₁-Antitrypsin augmentation therapy, used widely in North America and much of Europe, has been available for over 22 years and is given by

M* wars: conformational controversy regarding the pathological intermediate

The view that polymers form by the insertion of the reactive loop of one molecule into β-sheet A of another was held to be correct for 16 years (Figure 2B). However, in 2008, the consensus was challenged by crystal structures of a closed dimer of a related serpin antithrombin and then a trimer of a disulphide mutant of α₁-antitrypsin 69, 70. These structures suggested different conformational mechanisms (Figure 2C, D) that, together with the classical model, were mutually incompatible. However,

New delivery methods for augmentation therapy

Augmentation therapy as currently delivered requires regular (typically weekly) intravenous infusion of plasma-derived material. This has significant implications in terms of cost, is likely to impact on quality of life and makes augmentation dependent upon the overall commercial viability of plasma protein purification for therapeutic use (e.g., immunoglobulins, clotting factors, and albumin). Therefore, if the current general trend away from the use of other plasma products continues,

Connecting cell biology to human disease

The cellular handling of α₁-antitrypsin has been well characterised in eukaryotic cell models of disease, with some validation in transgenic mice, but the work raises further important questions. The mechanism and consequences of NFκB activation in cells expressing Z α₁-antitrypsin now require further clarification, as does the role of α₁-antitrypsin (both intracellular and exogenous) in cell survival and the importance of Z α₁-antitrypsin polymer accumulation within the lung. The field cannot

Concluding remarks

The careful work of Laurell and Eriksson, matching clinical laboratory investigations to disease phenotype, represented a template upon which successive rounds of methodical and elegant studies could be devised. The identification of the serpin superfamily and characterisation of how conformational change mediated biological function in its members, notably α₁-antitrypsin, was serendipitous in its timing. Together, these factors have placed α₁-antitrypsin deficiency (and by extension other

Acknowledgements

J.D. is a Medical Research Council (MRC) Clinical Research Training Fellow and the recipient of a Sackler Studentship. The work within the Lomas group is funded by the MRC (UK), GlaxoSmithKline, and the University College London National Institute of Health Research Biomedical Research Centre, and within the Gooptu group by the Alpha-1 Foundation. We acknowledge Professor Christine Slingsby (ISMB/Crystallography, Birkbeck, University of London, London, UK) for insightful conversations

Glossary

Amyloids: insoluble, fibrillar protein aggregates consisting of inappropriately folded proteins or polypeptides arranged in characteristic crossed β-structure. Deposition can be organ-specific or systemic. Mutations in the precursor protein can lead to inherited amyloidoses.
Autophagy regulator transcription factor EB (TFEB): a protein that resides on the lysosome membrane and regulates the autophagy–lysosome pathway. Upon activation it migrates to the nucleus and acts as a transcription factor,

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Capturing the conversion of the pathogenic alpha-1-antitrypsin fold by ATF6 enhanced proteostasis
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Genetic variation in alpha-1 antitrypsin (AAT) causes AAT deficiency (AATD) through liver aggregation-associated gain-of-toxic pathology and/or insufficient AAT activity in the lung manifesting as chronic obstructive pulmonary disease (COPD). Here, we utilize 71 AATD-associated variants as input through Gaussian process (GP)-based machine learning to study the correction of AAT folding and function at a residue-by-residue level by pharmacological activation of the ATF6 arm of the unfolded protein response (UPR). We show that ATF6 activators increase AAT neutrophil elastase (NE) inhibitory activity, while reducing polymer accumulation for the majority of AATD variants, including the prominent Z variant. GP-based profiling of the residue-by-residue response to ATF6 activators captures an unexpected role of the “gate” area in managing AAT-specific activity. Our work establishes a new spatial covariant (SCV) understanding of the convertible state of the protein fold in response to genetic perturbation and active environmental management by proteostasis enhancement for precision medicine.
Characterization of three new SERPINA1 variants PiQ0<inf>Heidelberg II</inf>, PiQ0<inf>Heidelberg III</inf> and PiQ0<inf>Heidelberg IV</inf> in patients with severe alpha-1 antitrypsin deficiency
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The clinical and molecular characteristics of three patients with previously unreported SERPINA1 mutations associated with severe alpha-1 antitrypsin deficiency (AATD) are described. The pathophysiology of the chronic obstructive pulmonary disease (COPD) present in these patients was characterized through clinical, biochemical, and genetic examinations.
Case 1: A 73-year-old male with bilateral centri-to panlobular emphysema and multiple increasing ventrobasal bullae and incomplete fissures, COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade III B), progressive dyspnea on exertion (DOE), AAT level of 0.1–0.2 g/L. Genetic testing revealed a unique SERPINA1 mutation: Pi*Z/c.1072C > T. This allele was designated PiQ0_{Heidelberg II}. Case 2: A 47-year-old male with severely heterogenous centri-to panlobular emphysema concentrated in the lower lobes, COPD GOLD IV D with progressive DOE, AAT <0.1 g/L. He also had a unique Pi*Z/c.10del mutation in SERPINA1. This allele was named PiQ0_{Heidelberg III}. Case 3: A 58-year-old female with basally accentuated panlobular emphysema, GOLD II B COPD, progressive DOE. AAT 0.1 g/L. Genetic analysis revealed Pi*Z/c.-5+1G > A and c.-472G > A mutations in SERPINA1. This variant allele was named PiQ0_{Heidelberg IV}.
Each of these patients had a unique and previously unreported SERPINA1 mutation. In two cases, AATD and a history of smoking led to severe lung disease. In the third case, timely diagnosis, and institution of AAT replacement stabilized lung function. Wider screening of COPD patients for AATD could lead to faster diagnosis and earlier treatment of AATD patients with AATD which could slow or prevent progression of their disease.
Evaluation of cytosine base editing and adenine base editing as a potential treatment for alpha-1 antitrypsin deficiency
2022, Molecular Therapy
Alpha-1 antitrypsin deficiency (AATD) is a rare autosomal codominant disease caused by mutations within the SERPINA1 gene. The most prevalent variant in patients is PiZ SERPINA1, containing a single G > A transition mutation. PiZ alpha-1 antitrypsin (AAT) is prone to misfolding, leading to the accumulation of toxic aggregates within hepatocytes. In addition, the abnormally low level of AAT secreted into circulation provides insufficient inhibition of neutrophil elastase within the lungs, eventually causing emphysema. Cytosine and adenine base editors enable the programmable conversion of C⋅G to T⋅A and A⋅T to G⋅C base pairs, respectively. In this study, two different base editing approaches were developed: use of a cytosine base editor to install a compensatory mutation (p.Met374Ile) and use of an adenine base editor to mediate the correction of the pathogenic PiZ mutation. After treatment with lipid nanoparticles formulated with base editing reagents, PiZ-transgenic mice exhibited durable editing of SERPINA1 in the liver, increased serum AAT, and improved liver histology. These results indicate that base editing has the potential to address both lung and liver disease in AATD.
Hepatocyte proteomes reveal the role of protein disulfide isomerase 4 in alpha 1-antitrypsin deficiency
2021, JHEP Reports
A single point mutation in the Z-variant of alpha 1-antitrypsin (Z-AAT) alone can lead to both a protein folding and trafficking defect, preventing its exit from the endoplasmic reticulum (ER), and the formation of aggregates that are retained as inclusions within the ER of hepatocytes. These defects result in a systemic AAT deficiency (AATD) that causes lung disease, whereas the ER-retained aggregates can induce severe liver injury in patients with ZZ-AATD. Unfortunately, therapeutic approaches are still limited and liver transplantation represents the only curative treatment option. To overcome this limitation, a better understanding of the molecular basis of ER aggregate formation could provide new strategies for therapeutic intervention.
Our functional and omics approaches here based on human hepatocytes from patients with ZZ-AATD have enabled the identification and characterisation of the role of the protein disulfide isomerase (PDI) A4/ERP72 in features of AATD-mediated liver disease.
We report that 4 members of the PDI family (PDIA4, PDIA3, P4HB, and TXNDC5) are specifically upregulated in ZZ-AATD liver samples from adult patients. Furthermore, we show that only PDIA4 knockdown or alteration of its activity by cysteamine treatment can promote Z-AAT secretion and lead to a marked decrease in Z aggregates. Finally, detailed analysis of the Z-AAT interactome shows that PDIA4 silencing provides a more conducive environment for folding of the Z mutant, accompanied by reduction of Z-AAT-mediated oxidative stress, a feature of AATD-mediated liver disease.
PDIA4 is involved in AATD-mediated liver disease and thus represents a therapeutic target for inhibition by drugs such as cysteamine. PDI inhibition therefore represents a potential therapeutic approach for treatment of AATD.
Protein disulfide isomerase (PDI) family members, and particularly PDIA4, are upregulated and involved in alpha 1-antitrypsin deficiency (AATD)-mediated liver disease in adults. PDI inhibition upon cysteamine treatment leads to improvements in features of AATD and hence represents a therapeutic approach for treatment of AATD-mediated liver disease.
Diagnosis and management of secondary causes of steatohepatitis
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The term non-alcoholic fatty liver disease (NAFLD) was originally coined to describe hepatic fat deposition as part of the metabolic syndrome. However, a variety of rare hereditary liver and metabolic diseases, intestinal diseases, endocrine disorders and drugs may underlie, mimic, or aggravate NAFLD. In contrast to primary NAFLD, therapeutic interventions are available for many secondary causes of NAFLD. Accordingly, secondary causes of fatty liver disease should be considered during the diagnostic workup of patients with fatty liver disease, and treatment of the underlying disease should be started to halt disease progression. Common genetic variants in several genes involved in lipid handling and metabolism modulate the risk of progression from steatosis to fibrosis, cirrhosis and hepatocellular carcinoma development in NAFLD, alcohol-related liver disease and viral hepatitis. Hence, we speculate that genotyping of common risk variants for liver disease progression may be equally useful to gauge the likelihood of developing advanced liver disease in patients with secondary fatty liver disease.
Cargo receptor-assisted endoplasmic reticulum export of pathogenic α1-antitrypsin polymers
2021, Cell Reports
Citation Excerpt :
Missense variants in SERPINA1, including the most common Z variant (E342K), perturb the stability and conformation of α1AT monomers, resulting in their intracellular retention and formation of ordered and pathogenic polymers that accumulate within the lumen of the endoplasmic reticulum (ER) of hepatocytes. Intracellular retention is the basis of plasma α1AT deficiency underlying early-onset emphysema (Gooptu et al., 2014). Accumulation of polymers within liver cells is also associated with a toxic gain-of-function that predisposes to neonatal hepatitis and hepatocellular carcinoma (Eriksson et al., 1986).
Circulating polymers of α1-antitrypsin (α1AT) are neutrophil chemo-attractants and contribute to inflammation, yet cellular factors affecting their secretion remain obscure. We report on a genome-wide CRISPR-Cas9 screen for genes affecting trafficking of polymerogenic α1AT^H334D. A CRISPR enrichment approach based on recovery of single guide RNA (sgRNA) sequences from phenotypically selected fixed cells reveals that cells with high-polymer content are enriched in sgRNAs targeting genes involved in “cargo loading into COPII-coated vesicles,” where “COPII” is coat protein II, including the cargo receptors lectin mannose binding1 (LMAN1) and surfeit protein locus 4 (SURF4). LMAN1- and SURF4-disrupted cells display a secretion defect extending beyond α1AT monomers to polymers. Polymer secretion is especially dependent on SURF4 and correlates with a SURF4-α1AT^H334D physical interaction and with their co-localization at the endoplasmic reticulum (ER). These findings indicate that ER cargo receptors co-ordinate progression of α1AT out of the ER and modulate the accumulation of polymeric α1AT not only by controlling the concentration of precursor monomers but also by promoting secretion of polymers.

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Trends in Molecular Medicine

ReviewThe molecular and cellular pathology of α1-antitrypsin deficiency

Highlights

Section snippets

From syndromics to mechanism: a half-century of characterisation

Physiological production and function of α1-antitrypsin

Polymerisation: the central feature of α1-antitrypsin deficiency

Quality control, ER-associated degradation, and the unfolded protein response

Current treatment approaches

M* wars: conformational controversy regarding the pathological intermediate

New delivery methods for augmentation therapy

Connecting cell biology to human disease

Concluding remarks

Acknowledgements

Glossary

Clin. Chim. Acta

Clin. Chim. Acta

Curr. Opin. Struct. Biol.

Lancet

J. Biol. Chem.

FEBS Lett.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Mol. Biol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Respir. Med.

Am. J. Pathol.

Chest

Lancet

Structure

J. Biol. Chem.

Lab. Invest.

Methods Enzymol.

J. Mol. Biol.

J. Biol. Chem.

The electrophoretic α1-globulin pattern of serum in α1-antitrypsin deficiency

Scand. J. Clin. Lab. Invest.

Studies in α1-antitrypsin deficiency

Acta Med. Scand.

Pulmonary emphysema and α1-antitrypsin deficiency

Acta Med. Scand.

Emphysema before and after 1963 – historic perspectives

Ann. N. Y. Acad. Sci.

Age of SERPINA1 gene PI Z mutation: Swedish and Latvian population analysis

Ann. Hum. Genet.

Prevalence of α1-antitrypsin deficiency alleles PI*S and PI*Z worldwide and effective screening for each of the five phenotypic classes PI*MS, PI*MZ, PI*SS, PI*SZ, and PI*ZZ: a comprehensive review

Ther. Adv. Respir. Dis.

α1-Antitrypsin-deficient variant Siiyama (Ser53[TCC] to Phe53[TTC]) is prevalent in Japan. Status of α1-antitrysin deficiency in Japan

Am. Rev. Respir. Dis.

PCR-based screening for the most prevalent α1 antitrypsin deficiency mutations (PI S, Z, and Mmalton) in COPD patients from Eastern Tunisia

Biochem. Genet.

Cirrhosis associated with α-1-antitrypsin deficiency: a previously unrecognised inherited disorder

J. Lab. Clin. Med.

Liver disease in α1-antitrypsin deficiency detected by screening of 200,000 infants

N. Engl. J. Med.

Risk of cirrhosis and primary liver cancer in α1-antitrypsin deficiency

N. Engl. J. Med.

Polymers and inflammation: disease mechanisms of the serpinopathies

J. Exp. Med.

Morphological identification of α-1-antitrypsin in the human small intestine

Histopathology

Activated neutrophils secrete stored α1-antitrypsin

Am. J. Respir. Crit. Care Med.

Interrelationships between the human alveolar macrophage and α-1-antitrypsin

J. Clin. Invest.

Structure of a serpin–protease complex shows inhibition by deformation

Nature

Mechanisms of emphysema in α1-antitrypsin deficiency: molecular and cellular insights

Eur. Respir. J.

Human neutrophil defensin and serpins form complexes and inactivate each other

Am. J. Respir. Cell Mol. Biol.

A novel antioptotic role for α1-antitrypsin in the prevention of pulmonary emphysema

Review
The molecular and cellular pathology of α₁-antitrypsin deficiency

Physiological production and function of α₁-antitrypsin

Polymerisation: the central feature of α₁-antitrypsin deficiency

The electrophoretic α₁-globulin pattern of serum in α₁-antitrypsin deficiency

Studies in α₁-antitrypsin deficiency

Pulmonary emphysema and α₁-antitrypsin deficiency

Prevalence of α₁-antitrypsin deficiency alleles PIS and PIZ worldwide and effective screening for each of the five phenotypic classes PIMS, PIMZ, PISS, PISZ, and PI*ZZ: a comprehensive review

α₁-Antitrypsin-deficient variant Siiyama (Ser⁵³[TCC] to Phe⁵³[TTC]) is prevalent in Japan. Status of α₁-antitrysin deficiency in Japan

PCR-based screening for the most prevalent α₁ antitrypsin deficiency mutations (PI S, Z, and M_malton) in COPD patients from Eastern Tunisia

Liver disease in α₁-antitrypsin deficiency detected by screening of 200,000 infants

Risk of cirrhosis and primary liver cancer in α₁-antitrypsin deficiency

Activated neutrophils secrete stored α₁-antitrypsin

Mechanisms of emphysema in α₁-antitrypsin deficiency: molecular and cellular insights

A novel antioptotic role for α₁-antitrypsin in the prevention of pulmonary emphysema

The mechanism of Z α₁-antitrypsin accumulation in the liver

Structural transition of α₁-antitrypsin by a peptide sequentially similar to β-strand s4A

Human α₁-proteinase inhibitor. Crystal structure analysis of two crystal modifications, molecular model and preliminary analysis of the implications for function