Back to Search
Start Over
Calreticulin enhances the secretory trafficking of a misfolded α-1-antitrypsin.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2020 Dec 04; Vol. 295 (49), pp. 16754-16772. Date of Electronic Publication: 2020 Sep 25. - Publication Year :
- 2020
-
Abstract
- α1-antitrypsin (AAT) regulates the activity of multiple proteases in the lungs and liver. A mutant of AAT (E342K) called ATZ forms polymers that are present at only low levels in the serum and induce intracellular protein inclusions, causing lung emphysema and liver cirrhosis. An understanding of factors that can reduce the intracellular accumulation of ATZ is of great interest. We now show that calreticulin (CRT), an endoplasmic reticulum (ER) glycoprotein chaperone, promotes the secretory trafficking of ATZ, enhancing the media:cell ratio. This effect is more pronounced for ATZ than with AAT and is only partially dependent on the glycan-binding site of CRT, which is generally relevant to substrate recruitment and folding by CRT. The CRT-related chaperone calnexin does not enhance ATZ secretory trafficking, despite the higher cellular abundance of calnexin-ATZ complexes. CRT deficiency alters the distributions of ATZ-ER chaperone complexes, increasing ATZ-BiP binding and inclusion body formation and reducing ATZ interactions with components required for ER-Golgi trafficking, coincident with reduced levels of the protein transport protein Sec31A in CRT-deficient cells. These findings indicate a novel role for CRT in promoting the secretory trafficking of a protein that forms polymers and large intracellular inclusions. Inefficient secretory trafficking of ATZ in the absence of CRT is coincident with enhanced accumulation of ER-derived ATZ inclusion bodies. Further understanding of the factors that control the secretory trafficking of ATZ and their regulation by CRT could lead to new therapies for lung and liver diseases linked to AAT deficiency.<br />Competing Interests: Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article.<br /> (© 2020 Mohan et al.)
- Subjects :
- Animals
Binding Sites
Calnexin deficiency
Calnexin genetics
Calnexin metabolism
Calreticulin deficiency
Calreticulin genetics
Cell Line
Endoplasmic Reticulum metabolism
Humans
Inclusion Bodies metabolism
Mice
Mutagenesis, Site-Directed
Polysaccharides chemistry
Polysaccharides metabolism
Protein Binding
Protein Folding
Vesicular Transport Proteins genetics
Vesicular Transport Proteins metabolism
alpha 1-Antitrypsin chemistry
alpha 1-Antitrypsin genetics
Calreticulin metabolism
Protein Transport physiology
alpha 1-Antitrypsin metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 295
- Issue :
- 49
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 32978262
- Full Text :
- https://doi.org/10.1074/jbc.RA120.014372