Regulator of G signaling 16 is a marker for the distinct endoplasmic reticulum stress state associated with aggregated mutant α1- antitrypsin Z in the classical form of α1-antitrypsin deficiency

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

Research output: Contribution to journalArticle

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Abstract

In the classical form of α1-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 α1-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 α1-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 non-polymerogenic α1-antitrypsin mutant accumulated in the ER. RGS16 was up-regulated in livers from patients with α1-antitrypsin deficiency, and the degree of up-regulation correlated with the hepatic levels of insoluble α1-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 α1-antitrypsin deficiency, presumably determined by the aggregation-prone properties of the mutant protein that characterizes the deficiency.

Original languageEnglish (US)
Pages (from-to)27769-27780
Number of pages12
JournalJournal of Biological Chemistry
Volume282
Issue number38
DOIs
StatePublished - Sep 21 2007

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Endoplasmic Reticulum Stress
Liver
Mutant Proteins
Endoplasmic Reticulum
Unfolded Protein Response
Gene expression
Up-Regulation
Tunicamycin
Calcium Ionophores
Poisons
Protein Deficiency
Autophagy
Transcriptome
Proteins
Agglomeration
Transgenic Mice
Carcinogenesis
Gene Expression

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Regulator of G signaling 16 is a marker for the distinct endoplasmic reticulum stress state associated with aggregated mutant α1- antitrypsin Z in the classical form of α1-antitrypsin deficiency. / Hidvegi, Tunda; Mirnics, Karoly; Hale, Pamela; Ewing, Michael; Beckett, Caroline; Perlmutter, David H.

In: Journal of Biological Chemistry, Vol. 282, No. 38, 21.09.2007, p. 27769-27780.

Research output: Contribution to journalArticle

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