The Sec7 Arf-GEF Is Recruited to the trans-Golgi Network by Positive Feedback

Arf GTPases are key regulators of both retrograde and anterograde traffic at the Golgi complex. The Golgi-localized Arf activators, Arf-GEFs (guanine exchange factor) of the BIG/GBF family, are poorly understood in terms of both their regulatory and localization mechanisms. We have performed a detailed kinetic characterization of a functional Golgi Arf-GEF, the trans-Golgi network (TGN)-localized Sec7 protein from yeast. We demonstrate that Sec7 is regulated by both autoinhibition and positive feedback. We show that positive feedback arises through the stable recruitment of Sec7 to membranes via its HDS1 domain by interaction with its product, activated Arf1. This interaction mediates localization of Sec7 to the TGN, because deletion of the HDS1 domain or mutation of the HDS1 domain in combination with deletion of Arf1 significantly increases cytoplasmic localization of Sec7. Our results lead us to propose a model in which Arf-GEF recruitment is linked to Golgi maturation via Arf1 activation. [Display omitted] ► The Golgi Arf-GEF Sec7 is regulated by autoinhibition and positive feedback ► Positive feedback results from stable recruitment of Sec7 to the membrane surface ► Positive feedback arises through interaction between the HDS1 domain and Arf1-GTP ► The HDS1 domain and Arf1 mediate recruitment of Sec7 to the trans-Golgi network Arf guanine exchange factors (GEFs) activate Arf GTPases, key regulators of trafficking at the Golgi complex. Richardson et al. show that the activity and localization of the Arf-GEF Sec7 is controlled through autoinhibition and positive feedback. The authors propose that active Arf1-mediated positive feedback links Arf-GEF recruitment to Golgi maturation.