Modulation of calreticulin expression reveals a novel exosome-mediated mechanism of Z variant 1 -antitrypsin disposal

Nazli Khodayari, Regina Oshins, Abdel A. Alli, Kubra M. Tuna, L. Shannon Holliday, Karina Krotova, Mark Brantly

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

1-Antitrypsin deficiency (AATD) is an inherited disease characterized by emphysema and liver disease. AATD is most often caused by a single amino acid substitution at position 342 in the mature protein, resulting in the Z mutation of the AAT gene (ZAAT). This substitution is associated with misfolding and accumulation of ZAAT in the endoplasmic reticulum (ER) of hepatocytes, causing a toxic gain of function. ERdj3 is an ER luminal DnaJ homologue, which, along with calreticulin, directly interacts with misfolded ZAAT. We hypothesize that depletion of each of these chaperones will change the fate of ZAAT polymers. Our study demonstrates that calreticulin modulation reveals a novel ZAAT degradation mechanism mediated by exosomes. Using human PiZZ hepatocytes and K42, a mouse calreticulin-deficient fibroblast cell line, our results show ERdj3 and calreticulin directly interact with ZAAT in PiZZ hepatocytes. Silencing calreticulin induces calcium independent ZAAT–ERdj3 secretion through the exosome pathway. This co-secretion decreases ZAAT aggregates within the ER of hepatocytes. We demonstrate that calreticulin has an inhibitory effect on exosome-mediated ZAAT–ERdj3 secretion. This is a novel ZAAT degradation process that involves a DnaJ homologue chaperone bound to ZAAT. In this context, calreticulin modulation may eliminate the toxic gain of function associated with aggregation of ZAAT in lung and liver, thus providing a potential new therapeutic approach to the treatment of AATD-related liver disease.

Original languageEnglish (US)
Pages (from-to)6240-6252
Number of pages13
JournalJournal of Biological Chemistry
Volume294
Issue number16
DOIs
StatePublished - Apr 19 2019

Bibliographical note

Funding Information:
This work was supported by a grant from the Alpha-1 Foundation and National Institutes of Health National Center for Advancing Translational Sciences Grant UL1 TR000064. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funding Information:
This work was supported by a grant from the Alpha-1 Foundation and National Institutes of Health National Center for Advancing Translational Sciences Grant UL1 TR000064. The authors declare that they have no con-flicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2019 Khodayari et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.

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