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J. Biol. Chem., Vol. 280, Issue 20, 20042-20050, May 20, 2005

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Phosducin-like Protein Regulates G-Protein Folding by Interaction with Tailless Complex Polypeptide-1

DEPHOSPHORYLATION OR SPLICING OF PhLP TURNS THE SWITCH TOWARD REGULATION OF G FOLDING^*

Jan Humrich, Christina Bermel, Moritz Bünemann, Linda Härmark, Robert Frost, Ursula Quitterer, and Martin J. Lohse

From the Institute of Pharmacology and Toxicology, University of Wuerzburg, Versbacher Strasse 9, Wuerzburg 97078, Germany

Phosducin-like protein (PhLP) exists in two splice variants PhLP_LONG (PhLP_L) and PhLP_SHORT (PhLP_S). Whereas PhLP_L directly inhibits G-stimulated signaling, the G -inhibitory mechanism of PhLP_S is not understood. We report here that inhibition of G signaling in intact HEK cells by PhLP_S was independent of direct G binding; however, PhLP_S caused down-regulation of G and G proteins. The down-regulation was partially suppressed by lactacystine, indicating the involvement of proteasomal degradation. N-terminal fusion of G or G with a dye-labeling protein resulted in their stabilization against down-regulation by PhLP_S but did not lead to a functional rescue. Moreover, in the presence of PhLP_S, stabilized G subunits did not coprecipitate with stabilized G subunits, suggesting that PhLP_S might interfere with G folding. PhLP_S and several truncated mutants of PhLP_S interacted with the subunit tailless complex polypeptide-1 (TCP-1) of the CCT chaperonin complex, which is involved in protein folding. Knock-down of TCP-1 in HEK cells by small interfering RNA also led to down-regulation of G. We therefore conclude that the strong inhibitory action of PhLP_S on G signaling is the result of a previously unrecognized mechanism of G-regulation, inhibition of G-folding by interference with TCP-1.

Received for publication, August 12, 2004 , and in revised form, March 1, 2005.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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