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Vol. 19, Issue 2, 572-586, February 2008

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Sequestration of Mutated 1-Antitrypsin into Inclusion Bodies Is a Cell-protective Mechanism to Maintain Endoplasmic Reticulum Function

Susana Granell^*, Giovanna Baldini, Sameer Mohammad^*, Vanessa Nicolin, Paola Narducci, Brian Storrie, and Giulia Baldini^*

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

Submitted June 21, 2007; Revised October 18, 2007; Accepted November 16, 2007
Monitoring Editor: Thomas Sommer

A variant 1-antitrypsin with E342K mutation has a high tendency to form intracellular polymers, and it is associated with liver disease. In the hepatocytes of individuals carrying the mutation, 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 whether they are protective to the cell. We found that in hepatoma cells, mutated 1-antitrypsin exited the ER and accumulated in IBs that were negative for autophagosomal and lysosomal markers, and contained several ER components, but not calnexin. Mutated 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 disulfide isomerase, inhibited formation of IBs and lead to retention of mutated 1-antitrypsin in the ER. In hepatoma cells, shift of mutated 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 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)

Abbreviations used: AAT, wild-type 1-antitrypsin; ATZ, mutated 1-antitrypsin E342K; ER, endoplasmic reticulum; GFP, green fluorescent protein; IB, inclusion body; N2A, mouse neuroblastoma Neuro2A; NHK, 1-antitrypsin null Hong Kong; PDI, protein-disulfide isomerase; ROI, region of interest; TIRFM, total internal reflection microscopy; UPR, unfolded protein response.

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