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Published ahead of print on March 18, 2005, doi:10.1165/rcmb.2005-0009OC

Am. J. Respir. Cell Mol. Biol., Volume 32, Number 6, June 2005, 521-530

A more recent version of this article appeared on June 1, 2005
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Submitted on January 6, 2005
Revised on March 16, 2005

A ProSP-C BRICHOS Domain Mutation Causes ER Stress, Proteasome Dysfunction, and Caspase 3 Activation

Surafel Mulugeta1*, Vu Nguyen1, Scott J Russo1, Madesh Muniswamy2, and Michael F Beers1

1 Lung Epithelial Cell Biology Laboratories, Pulmonary and Critical Care Division, University of Pennsylvania School of Medicine, Philadelphia, PA, USA, 2 Institute for Environmental Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

* To whom correspondence should be addressed. E-mail: mulugeta{at}mail.med.upenn.edu.

BRICHOS is a domain found in several proteins consisting of ~100 amino acids with sequence and structural similarities. Mutations in BRICHOS domain have been associated with both degenerative and proliferative diseases in several non-pulmonary organs, although the pathogenic mechanisms are largely undefined. Recently, several mutations in surfactant protein C (SP-C) mapping to the BRICHOS domain located within the proprotein (proSP-C) have been linked to interstitial lung diseases. In vitro expression of one of these BRICHOS mutants, the exon 4 deletion (hSP-C{Delta}exon4), promotes a dominant negative perinuclear aggregation of the protein. The present study characterizes the trafficking behavior and pathogenic consequences resulting from hSP-C{Delta}exon4 expression. Time-lapse and co-localization microscopy studies demonstrated EGFP/hSP-C{Delta}exon4 expression in calnexin-positive (ER) compartment with subsequent time- and concentration-dependent development of ubiquitinated perinuclear inclusion bodies followed by apoptosis. Compared to controls, EGFP/hSPC{Delta}exon4 promoted upregulation of multiple ER stress species, activated caspase 3, and induced annexin V binding. Furthermore, in GFP-u cells, hSP-C{Delta}exon4 directly inhibited proteasome activity. These results support a model whereby proSP-C BRICHOS mutations induce a dynamic toxic gain-of-function causing apoptotic cell death via both early ER accumulation leading to an exaggerated unfolded protein response and enhanced deposition of cellular aggregates associated with proteasome dysfunction.




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