The molecular species responsible for α1 -antitrypsin deficiency are suppressed by a small molecule chaperone
© 2020 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies..
The formation of ordered Z (Glu342Lys) α1 -antitrypsin polymers in hepatocytes is central to liver disease in α1 -antitrypsin deficiency. In vitro experiments have identified an intermediate conformational state (M*) that precedes polymer formation, but this has yet to be identified in vivo. Moreover, the mechanism of polymer formation and their fate in cells have been incompletely characterised. We have used cell models of disease in conjunction with conformation-selective monoclonal antibodies and a small molecule inhibitor of polymerisation to define the dynamics of polymer formation, accumulation and secretion. Pulse-chase experiments demonstrate that Z α1 -antitrypsin accumulates as short-chain polymers that partition with soluble cellular components and are partially secreted by cells. These precede the formation of larger, insoluble polymers with a longer half-life (10.9 ± 1.7 h and 20.9 ± 7.4 h for soluble and insoluble polymers, respectively). The M* intermediate (or a by-product thereof) was identified in the cells by a conformation-specific monoclonal antibody. This was completely abrogated by treatment with the small molecule, which also blocked the formation of intracellular polymers. These data allow us to conclude that the M* conformation is central to polymerisation of Z α1 -antitrypsin in vivo; preventing its accumulation represents a tractable approach for pharmacological treatment of this condition; polymers are partially secreted; and polymers exist as two distinct populations in cells whose different dynamics have likely consequences for the aetiology of the disease.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:288 |
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| Enthalten in: |
The FEBS journal - 288(2021), 7 vom: 29. Apr., Seite 2222-2237 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ronzoni, Riccardo [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 20.07.2021 Date Revised 28.02.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/febs.15597 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM316279307 |
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| 245 | 1 | 4 | |a The molecular species responsible for α1 -antitrypsin deficiency are suppressed by a small molecule chaperone |
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| 500 | |a Date Revised 28.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2020 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. | ||
| 520 | |a The formation of ordered Z (Glu342Lys) α1 -antitrypsin polymers in hepatocytes is central to liver disease in α1 -antitrypsin deficiency. In vitro experiments have identified an intermediate conformational state (M*) that precedes polymer formation, but this has yet to be identified in vivo. Moreover, the mechanism of polymer formation and their fate in cells have been incompletely characterised. We have used cell models of disease in conjunction with conformation-selective monoclonal antibodies and a small molecule inhibitor of polymerisation to define the dynamics of polymer formation, accumulation and secretion. Pulse-chase experiments demonstrate that Z α1 -antitrypsin accumulates as short-chain polymers that partition with soluble cellular components and are partially secreted by cells. These precede the formation of larger, insoluble polymers with a longer half-life (10.9 ± 1.7 h and 20.9 ± 7.4 h for soluble and insoluble polymers, respectively). The M* intermediate (or a by-product thereof) was identified in the cells by a conformation-specific monoclonal antibody. This was completely abrogated by treatment with the small molecule, which also blocked the formation of intracellular polymers. These data allow us to conclude that the M* conformation is central to polymerisation of Z α1 -antitrypsin in vivo; preventing its accumulation represents a tractable approach for pharmacological treatment of this condition; polymers are partially secreted; and polymers exist as two distinct populations in cells whose different dynamics have likely consequences for the aetiology of the disease | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a folding intermediate | |
| 650 | 4 | |a polymer inhibitor | |
| 650 | 4 | |a polymerisation | |
| 650 | 4 | |a secretion | |
| 650 | 4 | |a α1-antitrypsin | |
| 650 | 7 | |a Antibodies, Monoclonal |2 NLM | |
| 650 | 7 | |a Molecular Chaperones |2 NLM | |
| 650 | 7 | |a Polymers |2 NLM | |
| 650 | 7 | |a Small Molecule Libraries |2 NLM | |
| 650 | 7 | |a alpha 1-Antitrypsin |2 NLM | |
| 700 | 1 | |a Heyer-Chauhan, Nina |e verfasserin |4 aut | |
| 700 | 1 | |a Fra, Annamaria |e verfasserin |4 aut | |
| 700 | 1 | |a Pearce, Andrew C |e verfasserin |4 aut | |
| 700 | 1 | |a Rüdiger, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Miranda, Elena |e verfasserin |4 aut | |
| 700 | 1 | |a Irving, James A |e verfasserin |4 aut | |
| 700 | 1 | |a Lomas, David A |e verfasserin |4 aut | |
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