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J. Biol. Chem., Vol. 282, Issue 38, 27769-27780, September 21, 2007

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Regulator of G Signaling 16 Is a Marker for the Distinct Endoplasmic Reticulum Stress State Associated with Aggregated Mutant ₁-Antitrypsin Z in the Classical Form of ₁-Antitrypsin Deficiency^*

Tunda Hidvegi, Karoly Mirnics, Pamela Hale, Michael Ewing, Caroline Beckett, and David H. Perlmutter¹

From the Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15213 and the Department of Psychiatry and Kennedy Center for Human Development, Vanderbilt University, Nashville, Tennessee 37232

In the classical form of ₁-antitrypsin deficiency, a mutant protein accumulates in a polymerized form in the endoplasmic reticulum (ER) of liver cells causing liver damage and carcinogenesis by a gain-of-toxic function mechanism. Recent studies have indicated that the accumulation of mutant ₁-antitrypsin Z in the ER specifically activates the autophagic response but not the unfolded protein response and that autophagy plays a critical role in disposal of insoluble ₁-antitrypsin Z. In this study, we used genomic analysis of the liver in a novel transgenic mouse model with inducible expression to screen for changes in gene expression that would potentially define how the liver responds to accumulation of this mutant protein. There was no unfolded protein response. Of several distinct gene expression profiles, marked up-regulation of regulator of G signaling (RGS16) was particularly notable. RGS16 did not increase when model systems were exposed to classical inducers of ER stress, including tunicamycin and calcium ionophore, or when a nonpolymerogenic ₁-antitrypsin mutant accumulated in the ER. RGS16 was up-regulated in livers from patients with ₁-antitrypsin deficiency, and the degree of up-regulation correlated with the hepatic levels of insoluble ₁-antitrypsin Z protein. Taken together, these results indicate that expression of RGS16 is an excellent marker for the distinct form of "ER stress" that occurs in ₁-antitrypsin deficiency, presumably determined by the aggregation-prone properties of the mutant protein that characterizes the deficiency.

Received for publication, May 25, 2007 , and in revised form, July 2, 2007.

^* This work was supported in part by United States Public Health Service Grants HL037784 and DK052526 from the National Institutes of Health and the Alpha-One Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1 and Tables 1–4.

¹ To whom correspondence should be addressed: Dept. of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, 3705 Fifth Ave., Pittsburgh, PA 15213. Tel.: 412-692-8071; Fax: 412-692-5946; E-mail: David.Perlmutter{at}chp.edu.

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