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Sci. Signal., 22 November 2011
Vol. 4, Issue 200, p. ra79
[DOI: 10.1126/scisignal.2002223]

RESEARCH ARTICLES

Ric-8 Proteins Are Molecular Chaperones That Direct Nascent G Protein α Subunit Membrane Association

Meital Gabay1, Mary E. Pinter1, Forrest A. Wright1, PuiYee Chan1, Andrew J. Murphy2, David M. Valenzuela2, George D. Yancopoulos2, and Gregory G. Tall1*

1 Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642, USA.
2 Regeneron Pharmaceuticals Inc., Tarrytown, NY 10510, USA.

Abstract: 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 Gαi, Gαq, and Gα13 proteins to <5% of those of wild-type cells. The amounts of Gαs and total Gβ protein were partially reduced in Ric-8A–/– cells compared to those in wild-type cells, and only the amount of Gαs was reduced substantially in Ric-8B–/– cells. The abundances of mRNAs encoding the G protein α 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 Gαi and Gαq were efficiently translated in Ric-8A–/– cells but integrated into endomembranes poorly; however, the reduced amounts of G protein α subunits that reached the membrane still bound to nascent Gβ{gamma}. Finally, Gαi, Gαq, and Gβ1 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 Gα subunits with cellular membranes.

* To whom correspondence should be addressed. E-mail: gregory_tall{at}urmc.rochester.edu

Citation: M. Gabay, M. E. Pinter, F. A. Wright, P. Chan, A. J. Murphy, D. M. Valenzuela, G. D. Yancopoulos, G. G. Tall, Ric-8 Proteins Are Molecular Chaperones That Direct Nascent G Protein α Subunit Membrane Association. Sci. Signal. 4, ra79 (2011).

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