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

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.