The core domain of RGS16 retains G‐protein binding and GAP activity in vitro, but is not functional in vivo

Chen, Canhe; Lin, Sheng-Cai

doi:10.1016/s0014-5793(98)00042-8

Cited by 36 publications

(34 citation statements)

References 17 publications

(31 reference statements)

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“…This means that G␣ i3 mediates the hepatic anti-autophagic effect of insulin. Because RGS16 binds to G␣ i3 (21) and is thought to inhibit G signaling, one could hypothesize that induction of RGS16 when ATZ accumulates in the ER serves to inhibit a G␣ i3 -mediated signaling pathway and, in so doing, de-represses autophagy. Further evidence for this idea comes from studies of another member of the RGS family, AGS3.…”

Section: Discussionmentioning

confidence: 99%

“…It is possible that up-regulation of RGS16 is only one of several mechanisms by which autophagy is activated in AT deficiency and that it is not sufficient for activation of autophagy. Indeed, we already know that RGS5 expression is up-regulated and that RGS5 has some G␣ i3 antagonistic activity (21).…”

Section: Discussionmentioning

confidence: 99%

“…Fourth, up-regulation of RGS16 is potentially of great functional significance. It is known to bind to and inactivate G␣ i3 (21), and a recent study in a G␣ i3 knock-out mouse model provides evidence that G␣ i3 mediates the hepatic anti-autophagic effect of TOR kinase (22). Thus, up-regulation of RGS16 may be one of the ways that accumulation of ATZ in the liver activates the autophagic response.…”

Section: Up-regulation Of Rgs16 Gene Expression In the Liver In Respomentioning

confidence: 99%

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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

Mirnics

Hale

et al. 2007

Journal of Biological Chemistry

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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.The histological hallmark of the classical form of ␣ 1 -antitrypsin (AT) 2 deficiency is liver cells containing periodic acidSchiffϩ/diastase-resistant globules. From many years of research on the disease, we now know that these globules represent rough endoplasmic reticulum (ER) distended by accumulation of the mutant ATZ molecule (where ATZ is the Z variant of ␣ 1 -antitrypsin). The wild type AT is a classical liverderived secretory glycoprotein that is delivered by the circulating blood to tissues to subserve its predominant function of inhibiting the neutrophil serine proteases neutrophil elastase, cathepsin G, and proteinase 3. The point mutation that characterizes the ATZ variant converts glutamate 342 to lysine and is sufficient to result in selective retention of the glycoprotein in the ER (reviewed in Refs. 1, 2). Thus, AT deficiency could be considered a prototype, naturally occurring "ER stress" state. Characterization of the structure of AT and its functional correlates led to the remarkable observation that the substitution of lysine for glutamate 342 conferred on the ATZ molecule a tendency to polymerize and aggregate (3, 4). Although it is still not clear whether the tendency to polymerize is the cause, or an effect, of ER retention, there is clear-cut evidence that polymers and aggregates of this molecule are formed in the ER, and there is growing evidence that these polymers and aggregates play a role in how liver cells respond and wh...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Up-regulation Of Rgs16 Gene Expression In the Liver In Respomentioning

confidence: 99%

See 1 more Smart Citation

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

Mirnics

Hale

et al. 2007

Journal of Biological Chemistry

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“…This means that Gai3 mediates the hepatic antiautophagic effect of insulin. Because RGS16 (and RGS5) binds to and inhibits the activity of Gai3, 36 one could infer that upregulation of RGS16 when ATZ accumulates in the liver serves to inhibit signaling downstream from Gai3 and, in so doing, derepress autophagy ( Figure 3). Further evidence for this concept comes from studies of another member of the RGS family, AGS3.…”

Section: Potential Mechanisms For Activation Of Hepatic Autophagy In mentioning

confidence: 99%

Autophagic disposal of the aggregation-prone protein that causes liver inflammation and carcinogenesis in α-1-antitrypsin deficiency

Perlmutter

2008

Cell Death Differ

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ReviewAutophagic disposal of the aggregation-prone protein that causes liver inflammation and carcinogenesis in a-1-antitrypsin deficiency DH Perlmutter a-1-Antitrypsin (AT) deficiency is a relatively common autosomal co-dominant disorder, which causes chronic lung and liver disease. A point mutation renders aggregation-prone properties on a hepatic secretory protein in such a way that the mutant protein is retained in the endoplasmic reticulum of hepatocytes rather than secreted into the blood and body fluids where it ordinarily functions as an inhibitor of neutrophil proteases. A loss-of-function mechanism allows neutrophil proteases to degrade the connective tissue matrix of the lung causing chronic emphysema. Accumulation of aggregated mutant AT in the endoplasmic reticulum of hepatocytes causes liver inflammation and carcinogenesis by a gain-of-toxic function mechanism. However, genetic epidemiology studies indicate that many, if not the majority of, affected homozygotes are protected from liver disease by unlinked genetic and/or environmental modifiers. Studies performed over the last several years have demonstrated the importance of autophagy in disposal of mutant, aggregated AT and raise the possibility that predisposition to, or protection from, liver injury and carcinogenesis is determined by the balance of de novo biogenesis of the mutant AT molecule and its autophagic disposal.

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“…Therefore, the specific interaction with G␣ would be determined by divergent sequences outside of the RGS box. The first evidence that the RGS box alone might not be enough to function normally in vivo comes from the Sst2 complementation assay in yeast (53). The full-length RGS16 protein could bind and function as a GAP for G␣ i and G␣ o in vitro, and attenuated pheromone signaling.…”

Section: Fig 5 Southern Analysis Of Rgs18mentioning

confidence: 99%

Molecular Cloning and Characterization of a Novel Regulator of G-protein Signaling from Mouse Hematopoietic Stem Cells

Park¹,

Klug²,

Li³

et al. 2001

Journal of Biological Chemistry

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A novel regulator of G-protein signaling (RGS) has been isolated from a highly purified population of mouse long-term hematopoietic stem cells, and designated RGS18. It has 234 amino acids consisting of a central RGS box and short divergent NH 2 and COOH termini. The calculated molecular weight of RGS18 is 27,610 and the isoelectric point is 8.63. Mouse RGS18 is expressed from a single gene and shows tissue specific distribution. It is most highly expressed in bone marrow followed by fetal liver, spleen, and then lung. In bone marrow, RGS18 level is highest in long-term and shortterm hematopoietic stem cells, and is decreased as they differentiate into more committed multiple progenitors. The human RGS18 ortholog has a tissue-specific expression pattern similar to that of mouse RGS18. Purified RGS18 interacts with the ␣ subunit of both G i and G q subfamilies. The results of in vitro GTPase single-turnover assays using G␣ i indicated that RGS18 accelerates the intrinsic GTPase activity of G␣ i . Transient overexpression of RGS18 attenuated inositol phosphates production via angiotensin receptor and transcriptional activation through cAMP-responsive element via M1 muscarinic receptor. This suggests RGS18 can act on G q -mediated signaling pathways in vivo.A large number of extracellular stimuli act via cell surface receptors coupled to G-proteins (1). Inactive G-proteins are heterotrimeric proteins consisting of ␣, ␤, and ␥ subunits. Upon binding of a specific ligand to the G-protein-coupled receptor, the receptor promotes the exchange of GDP to GTP in the ␣ subunit, resulting in dissociation of the ␣ subunit from the ␤␥ subunits. The ␤␥ subunits are tightly associated and do not dissociate under physiological conditions. The free ␣ subunit and ␤␥ subunits then transmit signals through various signal transduction pathways. The activated ␣ subunit has slow intrinsic GTPase activity. When the ␣ subunit is in the GDPbound form, it re-associates with the ␤␥ subunits, leading to an inactive form. The duration of the G-protein signal depends on the rate of GTP hydrolysis and the rate of subunit re-association. For small GTP-binding proteins such as ras, there are GAP 1 proteins (GTPase activating protein), which increase the GTP hydrolysis rate. Recently, functional homologs of the ras-GAP have been identified for the heterotrimeric G-protein.These are called RGS (regulator of G-protein signaling) proteins. The first RGS identified, Sst2 (supersensitivity to pheromone) in yeast, is a negative regulator of pheromone signaling (2). Later, the SST2 gene product was shown to function as a GAP for Gpa1, a molecule involved in pheromone desensitization (3). So far ϳ20 RGS have been identified (4 -12), and more could be anticipated. All RGS proteins have a highly conserved domain consisting of 120 amino acid residues, the RGS box, with varying lengths of NH 2 and COOH termini. RGS4 can be expressed in bacteria, and it has been co-crystallized with G␣ i1 as the GDP-AlF4 Ϫ -bound form (13). It was shown that RGS binds to G␣ i t...

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The core domain of RGS16 retains G‐protein binding and GAP activity in vitro, but is not functional in vivo

Cited by 36 publications

References 17 publications

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

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

Autophagic disposal of the aggregation-prone protein that causes liver inflammation and carcinogenesis in α-1-antitrypsin deficiency

Molecular Cloning and Characterization of a Novel Regulator of G-protein Signaling from Mouse Hematopoietic Stem Cells

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