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MBC in Press, published online ahead of print July 18, 2007
Mol. Biol. Cell 10.1091/mbc.E07-01-0034

A more recent version of this article appeared on October 1, 2007
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Submitted on January 16, 2007
Revised on July 5, 2007
Accepted on July 9, 2007

ADD66, a Gene Involved in the Endoplasmic Reticulum Associated Degradation (ERAD) of Alpha-1-Antitrypsin-Z in Yeast, Facilitates Proteasome Activity and Assembly

Craig M. Scott,* Kristina B. Kruse,{dagger} Béla Z. Schmidt,{ddagger}{sect} David H. Perlmutter,{sect} Ardythe A. McCracken,{dagger} and Jeffrey L. Brodsky*

*Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260; {dagger}Department of Biology, University of Nevada, Reno, NV 89557; {sect}Department of Pediatrics, Cell Biology, and Physiology, University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh, Pittsburgh, PA 15213

Monitoring Editor: Peter Walter

Antitrypsin Deficiency is a primary cause of juvenile liver disease and arises from expression of the "Z" variant of the alpha-1 protease inhibitor (A1Pi). Whereas A1Pi is secreted from the liver, A1PiZ is retro-translocated from the endoplasmic reticulum (ER) and degraded by the proteasome, an event that may offset liver damage. To better define the mechanism of A1PiZ degradation, a yeast expression system was developed and a gene, ADD66, was identified that facilitates A1PiZ turn-over (Palmer et al., J. Cell. Sci. 116, 2361-2373, 2003). We report here that ADD66 encodes an ~30 kDa soluble, cytosolic protein and that the chymotrypsin-like activity of the proteasome is reduced in add66{Delta} mutants. This reduction in activity may arise from the accumulation of 20S proteasome assembly intermediates or from qualitative differences in assembled proteasomes. Add66p also appears to be a proteasome substrate. Consistent with its role in ER associated degradation (ERAD), synthetic interactions are observed between the genes encoding Add66p and Ire1p, a transducer of the unfolded protein response, and yeast deleted for both ADD66 and/or IRE1 accumulate polyubiquitinated proteins. These data identify Add66p as a proteasome assembly chaperone (PAC) and provide the first link between PAC activity and ERAD.

{ddagger}Present address: Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261.

Address correspondence to: Jeffrey L. Brodsky (jbrodsky{at}pitt.edu)






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