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MBC in Press, published online ahead of print November 28, 2007
Mol. Biol. Cell 10.1091/mbc.E07-06-0587

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Submitted on June 21, 2007
Revised on October 18, 2007
Accepted on November 16, 2007

Sequestration of Mutated {alpha}1-Antitrypsin Into Inclusion Bodies Is a Cell Protective Mechanism to Maintain Endoplasmic Reticulum Function

Susana Granell,* Giovanna Baldini,{dagger} Sameer Mohammad,* Vanessa Nicolin,{dagger} Paola Narducci,{dagger} Brian Storrie,{ddagger} and Giulia Baldini*

*Department of Biochemistry and Molecular Biology and {ddagger}Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR 72205; {dagger}Dipartimento Universitario Clinico di Biomedicina, Universita’ degli Studi di Trieste, Trieste I-34138, Italy

Monitoring Editor: Thomas Sommer

A variant {alpha}1-antitrypsin with E342K mutation has a high tendency to form intracellular polymers and is associated with liver disease. In the hepatocyte of individuals carrying the mutation, {alpha}1-antitrypsin localizes both to the endoplasmic reticulum (ER) and to membrane-surrounded inclusion bodies (IBs). It is unclear whether the IBs contribute to cell toxicity or are protective to the cell. We found that in hepatoma cells, mutated {alpha}1-antitrypsin exited the ER and accumulated in IBs that were negative for autophagosomal and lysosomal markers, contained several ER components, but not calnexin. Mutated {alpha}1-antitrypsin induced IBs also in neuroendocrine cells, showing that formation of these organelles is not cell-type specific. In the presence of IBs, ER function was largely maintained. Increased levels of calnexin, but not of protein disulphide isomerase, inhibited formation of IBs and lead to retention of mutated {alpha}1-antitrypsin in the ER. In hepatoma cells, shift of mutated {alpha}1-antitrypsin localization to the ER by calnexin overexpression lead to cell shrinkage, ER stress and impairment of the secretory pathway at the ER level. We conclude that segregation of mutated {alpha}1-antitrypsin from the ER to the IBs is a protective cell response to maintain a functional secretory pathway.

Address correspondence to: Giulia Baldini (Gbaldini{at}uams.edu)




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