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Vol. 18, Issue 7, 2646-2655, July 2007

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PI4P Promotes the Recruitment of the GGA Adaptor Proteins to the Trans-Golgi Network and Regulates Their Recognition of the Ubiquitin Sorting Signal

Jing Wang^*,, Hui-Qiao Sun^*,, Eric Macia, Tomas Kirchhausen, Hadiya Watson, Juan S. Bonifacino, and Helen L. Yin^*

*Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390; Department of Cell Biology and Center for Blood Research Institute for Biomedical Research, Harvard Medical School, Boston, MA 02115; and Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892

Submitted October 5, 2006; Revised April 3, 2007; Accepted April 26, 2007
Monitoring Editor: Sandra Schmid

Phosphatidylinositol 4 phosphate (PI4P) is highly enriched in the trans-Golgi network (TGN). Here we establish that PI4P is a key regulator of the recruitment of the GGA clathrin adaptor proteins to the TGN and that PI4P has a novel role in promoting their recognition of the ubiquitin (Ub) sorting signal. Knockdown of PI4KII by RNA interference (RNAi), which depletes the TGN's PI4P, impaired the recruitment of the GGAs to the TGN. GGAs bind PI4P primarily through their GAT domain, in a region called C-GAT, which also binds Ub but not Arf1. We identified two basic residues in the GAT domain that are essential for PI4P binding in vitro and for the recruitment of GGAs to the TGN in vivo. Unlike wild-type GGA, GGA with mutated GATs failed to rescue the abnormal TGN phenotype of the GGA RNAi-depleted cells. These residues partially overlap with those that bind Ub, and PI4P increased the affinity of the GAT domain for Ub. Because the recruitment of clathrin adaptors and their cargoes to the TGN is mediated through a web of low-affinity interactions, our results show that the dual roles of PI4P can promote specific GGA targeting and cargo recognition at the TGN.

These authors contributed equally to this work.

Address correspondence to: Helen L. Yin (Yin{at}UTSouthwestern.edu)

Abbreviations used: PI4P, phosphatidylinositol 4-phosphate; PI4KII, phosphatidylinositol 4-kinase type II; TGN, trans-Golgi network; GGA, Golgi-localized, -ear containing, ADP-ribosylation factor binding protein; GAT, GGA and Tom1 domain; C-GAT, C-terminal GAT; N-GAT, N-terminal GAT; VHS, Vps-27, Hrs, and STAM domain; Arf1, ADP-ribosylation factor 1; Ub, ubiquitin; PS, phosphatidylserine; PC, phosphatidylcholine; PE, phosphatidylethanolamine; ITC, isothermal titration calorimetry.

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