A Naturally Occurring Splice Variant of GGA1 Inhibits the Anterograde Post-Golgi Traffic of α(2B)-Adrenergic Receptor

The regulatory mechanisms of cell surface targeting of nascent G protein-coupled receptors (GPCRs) en route from the endoplasmic reticulum through the Golgi remain poorly understood. We have recently demonstrated that three Golgi-localized, γ-adaptin ear domain homology, ADP ribosylation factor-binding proteins (GGAs) mediate the post-Golgi export of α(2B)-adrenergic receptor (α(2B)-AR), a prototypic GPCR, and directly interact with the receptor. In particular, GGA1 interaction with α(2B)-AR is mediated via its hinge domain. Here we determined the role of a naturally occurring truncated form of GGA1 (GGA1t) which lacks the N-terminal portion of the hinge domain in α(2B)-AR trafficking and elucidated the underlying mechanisms. We demonstrated that both GGA1 and GGA1t were colocalized and mainly expressed at the Golgi. In marked contrast to GGA1, the expression of GGA1t significantly attenuated the cell surface export of newly synthesized α(2B)-AR from the Golgi and in parallel receptor-mediated signaling. Furthermore, we found that GGA1t formed homodimers and heterodimers with GGA1. More interestingly, GGA1t was unable to bind the cargo α(2B)-AR and to recruit clathrin onto the trans-Golgi network. These data provide evidence implicating that the truncated form of GGA1 behaviors as a dominant-negative regulator for the cell surface export of α(2B)-AR and this function of GGA1t is attributed to its abilities to dimerize with its wide type counterpart and to inhibit cargo interaction and clathrin recruitment to form specialized transport vesicles.