| First Author | Gabay M | Year | 2011 |
| Journal | Sci Signal | Volume | 4 |
| Issue | 200 | Pages | ra79 |
| PubMed ID | 22114146 | Mgi Jnum | J:260189 |
| Mgi Id | MGI:6142719 | Doi | 10.1126/scisignal.2002223 |
| Citation | Gabay M, et al. (2011) Ric-8 proteins are molecular chaperones that direct nascent G protein alpha subunit membrane association. Sci Signal 4(200):ra79 |
| abstractText | Ric-8A (resistance to inhibitors of cholinesterase 8A) and Ric-8B are guanine nucleotide exchange factors that enhance different heterotrimeric guanine nucleotide-binding protein (G protein) signaling pathways by unknown mechanisms. Because transgenic disruption of Ric-8A or Ric-8B in mice caused early embryonic lethality, we derived viable Ric-8A- or Ric-8B-deleted embryonic stem (ES) cell lines from blastocysts of these mice. We observed pleiotropic G protein signaling defects in Ric-8A(-/-) ES cells, which resulted from reduced steady-state amounts of Galpha(i), Galpha(q), and Galpha(13) proteins to <5% of those of wild-type cells. The amounts of Galpha(s) and total Gbeta protein were partially reduced in Ric-8A(-/-) cells compared to those in wild-type cells, and only the amount of Galpha(s) was reduced substantially in Ric-8B(-/-) cells. The abundances of mRNAs encoding the G protein alpha subunits were largely unchanged by loss of Ric-8A or Ric-8B. The plasma membrane residence of G proteins persisted in the absence of Ric-8 but was markedly reduced compared to that in wild-type cells. Endogenous Galpha(i) and Galpha(q) were efficiently translated in Ric-8A(-/-) cells but integrated into endomembranes poorly; however, the reduced amounts of G protein alpha subunits that reached the membrane still bound to nascent Gbetagamma. Finally, Galpha(i), Galpha(q), and Gbeta(1) proteins exhibited accelerated rates of degradation in Ric-8A(-/-) cells compared to those in wild-type cells. Together, these data suggest that Ric-8 proteins are molecular chaperones required for the initial association of nascent Galpha subunits with cellular membranes. |
