Promotion of Gαi3 subunit down-regulation by GIPN, a putative E3 ubiquitin ligase that interacts with RGS-GAIP

Vries, Luc De; Meerloo, Timo; Farquhar, Marilyn G.

doi:10.1073/pnas.1432965100

Cited by 67 publications

(45 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, the mutations we have described here may be useful in studying G␣ i as a potential ubiquitination substrate. Notably, G␣ i has been shown to be down-regulated by the overexpression of GIPN (GAIP interacting protein N terminus), a putative E3 ubiquitin ligase that is localized to the plasma membrane (50). The Medusa protein-modeling suite could also be used to study the effects of protein misfolding on other signaling proteins that share high similarity between organisms.…”

Section: Discussionmentioning

confidence: 99%

G Protein Mono-ubiquitination by the Rsp5 Ubiquitin Ligase

Torres¹,

Lee²,

Ding

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

Emerging evidence suggests that ubiquitination serves as a protein trafficking signal in addition to its well characterized role in promoting protein degradation. The yeast G protein ␣ subunit Gpa1 represents a rare example of a protein that undergoes both mono-and poly-ubiquitination. Whereas mono-ubiquitinated Gpa1 is targeted to the vacuole, poly-ubiquitinated Gpa1 is directed instead to the proteasome. Here we investigate the structural requirements for mono-and poly-ubiquitination of Gpa1. We find that variants of Gpa1 engineered to be unstable are more likely to be poly-ubiquitinated and less likely to be mono-ubiquitinated. In addition, mutants that cannot be myristoylated are no longer mono-ubiquitinated but are still polyubiquitinated. Finally, we show that the ubiquitin ligase Rsp5 is necessary for Gpa1 mono-ubiquitination in vivo and that the purified enzyme is sufficient to catalyze Gpa1 mono-ubiquitination in vitro. Taken together, these data indicate that mono-and poly-ubiquitination have distinct enzyme and substrate recognition requirements; whereas poly-ubiquitination targets misfolded protein for degradation, a distinct ubiquitination apparatus targets the fully mature, fully myristoylated G protein for mono-ubiquitination and delivery to the vacuole.

show abstract

Section: Discussionmentioning

confidence: 99%

G Protein Mono-ubiquitination by the Rsp5 Ubiquitin Ligase

Torres¹,

Lee²,

Ding

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Moreover, the membrane-bound pool of GAIP is phosphorylated in the N-terminus (Fischer et al, 2000), and at Ser151 that lies inside the RGS domain (Ogier-Denis et al, 2000). The RGS-Rz subfamily binds with the dileucine-rich region of GIPN (GAIP interacting protein N terminus), a putative E3 ubiquitin ligase that links the RGS-Rz proteins with Ga degradation (Fischer et al, 2003). Since GPCR agonists can increase the rate of Ga subunit degradation (Levis and Bourne, 1992;Wise et al, 1995), the retention of Ga subunits by RGS-Rz proteins might precede their degradation via the proteosome pathway.…”

Section: Discussionmentioning

confidence: 99%

The RGSZ2 Protein Exists in a Complex with μ-Opioid Receptors and Regulates the Desensitizing Capacity of Gz Proteins

Garzón

Rodríguez-Muñoz

López-Fando

et al. 2005

Neuropsychopharmacol

104

View full text Add to dashboard Cite

The regulator of G-protein signaling RGS17(Z2) is a member of the RGS-Rz subfamily of GTPase-activating proteins (GAP) that efficiently deactivate GazGTP subunits. We have found that in the central nervous system (CNS), the levels of RGSZ2 mRNA and protein are elevated in the hypothalamus, midbrain, and pons-medulla, and that RGSZ2 is glycosylated in synaptosomal membranes isolated from CNS tissue. In analyzing the function of RGSZ2 in the CNS, we found that when the expression of RGSZ2 was impaired, the antinociceptive response to morphine and [D-Ala 2 , N-MePhe 4 , Gly-ol 5 ]-enkephalin (DAMGO) augmented. This potentiation involved m-opioid receptors and increased tolerance to further doses of these agonists administered 24 h later. High doses of morphine promoted agonist desensitization even within the analgesia time-course, a phenomenon that appears to be related to the great capacity of morphine to activate Gz proteins. In contrast, the knockdown of RGSZ2 proteins did not affect the activity of d receptor agonists, [D-Pen 2,5 ]-enkephalin (DPDPE), and [D-Ala 2 ] deltorphin II. In membranes from periaqueductal gray matter (PAG), both RGSZ2 and the related RGS20(Z1) co-precipitated with m-opioid receptors. While a morphine challenge reduced the association of Gi/o/z with m receptors, it increased their association with the RGSZ2 and RGSZ1 proteins. However, only Gaz subunits co-precipitated with RGSZ2. Doses of morphine that produced acute tolerance maintained the association of Ga subunits with RGSZ proteins even after the analgesic effects had ceased. These results indicate that both RGSZ1 and RGSZ2 proteins influence m receptor signaling by sequestering Ga subunits, therefore behaving as effector antagonists.

show abstract

“…It is possible that the retention of G␣ subunits by RGS9-2 proteins precedes their degradation via the proteasome pathway. This seems to apply to the RGS-Rz subfamily, which binds to the dileucine-rich region of GIPN (GAIP-interacting protein N terminus), a putative ubiquitinprotein isopeptide ligase that links these RGS proteins with G␣ degradation (59). Since functional opioid tolerance produced by single doses lasts for several days, new synthesis of G␣ subunits would help to restore the control responses (6,31).…”

Section: Discussionmentioning

confidence: 99%

Activation of μ-Opioid Receptors Transfers Control of Gα Subunits to the Regulator of G-protein Signaling RGS9-2

Garzón

Rodríguez-Muñoz

López-Fando

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

In mouse periaqueductal gray matter (PAG) membranes, the -opioid receptor (MOR) coprecipitated the ␣-subunits of the G i/o/z/q/11 proteins, the G␤ 1/2 subunits, and the regulator of G-protein signaling RGS9-2 and its partner protein G␤ 5 . RGS7 and RGS11 present in this neural structure showed no association with MOR. In vivo intracerebroventricular injection of morphine did not alter MOR immunoreactivity, but 30 min and 3 h after administration, the coprecipitation of G␣ subunits with MORs was reduced by up to 50%. Furthermore, the association between G␣ subunits and RGS9-2 proteins was increased. Twenty-four hours after receiving intracerebroventricular morphine, the G␣ subunits left the RGS9-2 proteins and re-associated with the MORs. However, doses of the opioid able to induce tolerance promoted the stable transfer of G␣ subunits to the RGS9-2 control. This was accompanied by Ser phosphorylation of RGS9-2 proteins, which increased their coprecipitation with 14-3-3 proteins. In the PAG membranes of morphine-desensitized mice, the capacity of the opioid to stimulate G-protein-related guanosine 5- O-(3-[35 S]thiotriphosphate) binding as well as low K m GTPase activity was attenuated. The in vivo knockdown of RGS9-2 expression prevented morphine from altering the association between MORs and G-proteins, and tolerance did not develop. In PAG membranes from RGS9-2 knockdown mice, morphine showed full capacity to activate G-proteins. Thus, the tolerance that develops following an adequate dose of morphine is caused by the stabilization and retention of MOR-activated G␣ subunits by RGS9-2 proteins. This multistep process is initiated by the morphine-induced transfer of MOR-associated G␣ subunits to the RGS9-2 proteins, followed by Ser phosphorylation of the latter and their binding to 14-3-3 proteins. This regulatory mechanism probably precedes the loss of MORs from the cell membrane, which has been observed with other opioid agonists.

show abstract

Promotion of Gαi3 subunit down-regulation by GIPN, a putative E3 ubiquitin ligase that interacts with RGS-GAIP

Cited by 67 publications

References 46 publications

G Protein Mono-ubiquitination by the Rsp5 Ubiquitin Ligase

G Protein Mono-ubiquitination by the Rsp5 Ubiquitin Ligase

The RGSZ2 Protein Exists in a Complex with μ-Opioid Receptors and Regulates the Desensitizing Capacity of Gz Proteins

Activation of μ-Opioid Receptors Transfers Control of Gα Subunits to the Regulator of G-protein Signaling RGS9-2

Contact Info

Product

Resources

About