The pathogenic Z variant of the alpha-1 antitrypsin (AAT) protein leads to hypersensitivity to endoplasmic reticulum stress due to the immobilization of the endoplasmic reticulum chaperones within the polymer matrix, as published in Science Advances. This is a previously unidentified mechanism of endoplasmic reticulum dysfunction, which help better understand the pathology of AAT deficiency (AATD) and other related proteinopathies.

This new knowledge also suggests that endoplasmic reticulum chaperones could be potential therapeutic targets for AATD and other proteinopathies.

It is known that secretory proteins misfold in the endoplasmic reticulum in many proteinopathies. For example, in AATD the Z variant forms polymers in the endoplasmic reticulum of the hepatocytes and leads to cirrhosis.


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To better understand how the accumulation of polymerized Z-AAT affects the function of the endoplasmic reticulum, a team of researchers led by Stefan J. Marciniak, PhD, MB BChir, FRCP, MA, from Cambridge Institute for Medical Research in England characterized the mobility of AAT and other proteins in the endoplasmic reticulum of live cells.

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They found that AAT polymers undergo a liquid:solid phase transition and form a protein matrix. This matrix delays the mobility of endoplasmic reticulum proteins by size-dependent molecular filtration.

In the case of the pathogenic AAT Z variant, an ATF6-mediated unfolded protein response promotes this phase transition. ATF6 or activation transcription factor 6 is a stress sensor on the membrane of the endoplasmic reticulum.

Moreover, the researcher also showed that the endoplasmic reticulum chaperone calreticulin promotes the solidification of Z-AAT in the endoplasmic reticulum appears normal and is assumed to be healthy. Calreticulin also increases the stiffness of the protein matrix. These findings suggest that targeting calreticulin could have therapeutic effects on AATD.

AATD is caused by mutations in the SERPINA1 gene, which disrupts the normal production of AAT protein, the role of which is to form a protective screen in the lungs to protect the alveolar wall from the effect of neutrophil elastase.

Reference

Chambers JC, Zubikov N, Kubánková M, et al. Z-α1-antitrypsin polymers impose molecular filtration in the endoplasmic reticulum after undergoing phase transition to a solid state. Sci Adv. 2022;8:14. doi:10.1126/sciadv.abm2094