Ronzoni, R;
Heyer‐Chauhan, N;
Fra, A;
Pearce, AC;
Rüdiger, M;
Miranda, E;
Irving, JA;
(2020)
The molecular species responsible for α₁‐antitrypsin deficiency are suppressed by a small molecule chaperone.
The FEBS Journal
10.1111/febs.15597.
(In press).
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Abstract
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 polymerization 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 byproduct 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 polymerization 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.
| Type: | Article |
|---|---|
| Title: | The molecular species responsible for α₁‐antitrypsin deficiency are suppressed by a small molecule chaperone |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1111/febs.15597 |
| Publisher version: | https://doi.org/10.1111/febs.15597 |
| Language: | English |
| Additional information: | This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | α1‐antitrypsin, polymerisation, folding intermediate, polymer inhibitor, secretion |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Respiratory Medicine UCL > Provost and Vice Provost Offices > VP: Health |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10112819 |
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