Intrahepatic heteropolymerization of M and Z alpha-1-antitrypsin

Laffranchi, Mattia; Elliston, Emma; Miranda, Elena; Pérez, Juan; Ronzoni, Riccardo; Jagger, Alistair M.; Heyer-Chauhan, Nina; Brantly, Mark; Fra, Annamaria; Lomas, David A.; Irving, James A.

doi:10.1172/jci.insight.135459

Cited by 19 publications

(22 citation statements)

References 57 publications

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“…By analogy, the same holds true for AATD in which heteropolymers (M or S and Z) are entrapped within the RER, as recently demonstrated by confocal microscopy [64].…”

Section: Hereditary Hypofibrinogenemia With Hepatic Storage (Hhhs)supporting

confidence: 54%

“…Starzl observed a reduction of the amounts of AAT storage in Pi Z cirrhotic patients after porto-caval shunt [ 62 ], thereby suggesting that a proportion of Z AAT could be progressively released into the circulation, albeit at a lower sped than normal protein [ 31 ]. This phenomenon is potentially relevant in view of the recent demonstration that ZZ AAT homopolymers can be secreted from cells through the canonical secretory pathway [ 63 ], or that heteropolymers (M or S and Z AAT) can be found in ER and in circulation [ 64 ].…”

Section: Hereditary Hypofibrinogenemia With Hepatic Storage (Hhhs)mentioning

confidence: 99%

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The Discovery of Endoplasmic Reticulum Storage Disease. The Connection between an H&E Slide and the Brain

Callea

Desmet

2021

IJMS

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The revolutionary evolution in science and technology over the last few decades has made it possible to face more adequately three main challenges of modern medicine: changes in old diseases, the appearance of new diseases, and diseases that are unknown (mostly genetic), despite research efforts. In this paper we review the road travelled by pathologists in search of a method based upon the use of routine instruments and techniques which once were available for research only. The application to tissue studies of techniques from immunology, molecular biology, and genetics has allowed dynamic interpretations of biological phenomena with special regard to gene regulation and expression. That implies stepwise investigations, including light microscopy, immunohistochemistry, in situ hybridization, electron microscopy, molecular histopathology, protein crystallography, and gene sequencing, in order to progress from suggestive features detectable in routinely stained preparations to more characteristic, specific, and finally, pathognomonic features. Hematoxylin and Eosin (H&E)-stained preparations and appropriate immunohistochemical stains have enabled the recognition of phenotypic changes which may reflect genotypic alterations. That has been the case with hepatocytic inclusions detected in H&E-stained preparations, which appeared to correspond to secretory proteins that, due to genetic mutations, were retained within the rough endoplasmic reticulum (RER) and were deficient in plasma. The identification of this phenomenon affecting the molecules alpha-1-antitrypsin and fibrinogen has led to the discovery of a new field of cell organelle pathology, endoplasmic reticulum storage disease(s) (ERSD). Over fifty years, pathologists have wandered through a dark forest of complicated molecules with strange conformations, and by detailed observations in simple histopathological sections, accompanied by a growing background of molecular techniques and revelations, have been able to recognize and identify arrays of grotesque polypeptide arrangements.

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“…By analogy, the same holds true for AATD in which heteropolymers (M or S and Z) are entrapped within the RER, as recently demonstrated by confocal microscopy [64].…”

Section: Hereditary Hypofibrinogenemia With Hepatic Storage (Hhhs)supporting

confidence: 54%

Section: Hereditary Hypofibrinogenemia With Hepatic Storage (Hhhs)mentioning

confidence: 99%

The Discovery of Endoplasmic Reticulum Storage Disease. The Connection between an H&E Slide and the Brain

Callea

Desmet

2021

IJMS

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“…However, a recent study concerning structural characterization of AAT polymers obtained from post-transplant liver tissue of patients with the ZZ variant of AAT greatly favored the C-terminal Approximately 2-5% of Europeans are heterozygous for the Z and wild-type M alleles. Remarkably, a recent study elegantly demonstrated that the Z and M forms of AAT can copolymerize [68]. These data showed that Z-AAT can form heteropolymers with polymerization-inert variants in vivo, which has implications for liver disease in heterozygous individuals.…”

Section: Polymers Of Aatmentioning

confidence: 87%

Post-Translational Modifications of Circulating Alpha-1-Antitrypsin Protein

Lechowicz¹,

Rudzinski²,

Jezela‐Stanek³

et al. 2020

IJMS

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Alpha-1-antitrypsin (AAT), an acute-phase protein encoded by the SERPINA1 gene, is a member of the serine protease inhibitor (SERPIN) superfamily. Its primary function is to protect tissues from enzymes released during inflammation, such as neutrophil elastase and proteinase 3. In addition to its antiprotease activity, AAT interacts with numerous other substances and has various functions, mainly arising from the conformational flexibility of normal variants of AAT. Therefore, AAT has diverse biological functions and plays a role in various pathophysiological processes. This review discusses major molecular forms of AAT, including complex, cleaved, glycosylated, oxidized, and S-nitrosylated forms, in terms of their origin and function.

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“…The authenticity of the immunomorphological findings in Pi MZ livers, has been confirmed by comparing consecutive sections alternatively stained. Whether these findings allow the interpretation of a colocalization of Z and M AAT in the form of heteropolymers is highly suggestive in view of recognized phenomenon of AAT heteropolymerizations [28], recently culminated in the demonstration that Z AAT can form heteropolymers with wild type M AAT, thus leading to an increased intracellular concentration of M AAT. That is the requirement for detecting M AAT in paraffin embedded material with a polyclonal anti-AAT antibody.…”

Section: The "R-sb" Phenomenon and M And Z Heteropolymersmentioning

confidence: 93%

The Recruitment-Secretory Block (“R-SB”) Phenomenon and Endoplasmic Reticulum Storage Diseases

Callea

Tomà

Bellacchio

2021

IJMS

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In this article, we review the biological and clinical implication of the Recruitment-Secretory Block (“R-SB”) phenomenon. The phenomenon refers to the reaction of the liver with regard to protein secretion in conditions of clinical stimulation. Our basic knowledge of the process is due to the experimental work in animal models. Under basal conditions, the protein synthesis is mainly carried out by periportal (zone 1) hepatocytes that are considered the “professional” synthesizing protein cells. Under stimulation, midlobular and centrolobular (zone 2 and 3) hepatocytes, are progressively recruited according to lobular gradients and contribute to the increase of synthesis and secretion. The block of secretion, operated by exogenous agents, causes intracellular retention of all secretory proteins. The Pi MZ phenotype of Alpha-1-antitrypsin deficiency (AATD) has turned out to be the key for in vivo studies of the reaction of the liver, as synthesis and block of secretion are concomitant. Indeed, the M fraction of AAT is stimulated for synthesis and regularly exported while the Z fraction is mostly retained within the cell. For that reason, the phenomenon has been designated “Recruitment-Secretory Block” (“R-SB”). The “R-SB” phenomenon explains why: (a) the MZ individuals can correct the serum deficiency; (b) the resulting immonohistochemical and electron microscopic (EM) patterns are very peculiar and specific for the diagnosis of the Z mutation in tissue sections in the absence of genotyping; (c) the term carrier is no longer applicable for the heterozygous condition as all Pi MZ individuals undergo storage and the storage predisposes to liver damage. The storage represents the true elementary lesion and consequently reflects the phenotype-genotype correlation; (d) the site and function of the extrahepatic AAT and the relationship between intra and extracellular AAT; (e) last but not least, the concept of Endoplasmic Reticulum Storage Disease (ERSD) and of a new disease, hereditary hypofibrinogenemia with hepatic storage (HHHS). In the light of the emerging phenomenon, described in vitro, namely that M and Z AAT can form heteropolymers within hepatocytes as well as in circulation, we have reviewed the whole clinical and experimental material collected during forty years, in order to evaluate to what extent the polymerization phenomenon occurs in vivo. The paper summarizes similarities and differences between AAT and Fibrinogen as well as between the related diseases, AATD and HHHS. Indeed, fibrinogen gamma chain mutations undergo an aggregation process within the RER of hepatocytes similar to AATD. In addition, this work has clarified the intriguing phenomenon underlying a new syndrome, hereditary hypofibrinogenemia and hypo-APO-B-lipoproteinemia with hepatic storage of fibrinogen and APO-B lipoproteins. It is hoped that these studies could contribute to future research and select strategies aimed to simultaneously correct the hepatocytic storage, thus preventing the liver damage and the plasma deficiency of the two proteins.

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Intrahepatic heteropolymerization of M and Z alpha-1-antitrypsin

Cited by 19 publications

References 57 publications

The Discovery of Endoplasmic Reticulum Storage Disease. The Connection between an H&E Slide and the Brain

The Discovery of Endoplasmic Reticulum Storage Disease. The Connection between an H&E Slide and the Brain

Post-Translational Modifications of Circulating Alpha-1-Antitrypsin Protein

The Recruitment-Secretory Block (“R-SB”) Phenomenon and Endoplasmic Reticulum Storage Diseases

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