Shanshan He 1 , Duojiao Ni 1 , Binyun Ma 1 , Joo-Hyung Lee 1 , Tian Zhang 1 , Irene Ghozalli 1 , Sara Dolatshahi Pirooz 1 , Zhen Zhao 1 , Nagakumar Bharatham 2 , Baihong Li 2 , Soohwan Oh 1 , Wen-Hwa Lee 3 , Yoshinori Takahashi 4 , Hong-Gang Wang 4 , Arlet Minassian 1 , Pinghui Feng 1 , Vojo Deretic 5 , Rainer Pepperkok 6 , Mitsuo Tagaya 7 , Ho Sup Yoon 2 , 8 , Chengyu Liang 1 , *
22 September 2013
ER-Golgi membrane transport and autophagy are intersecting trafficking pathways that are tightly regulated and crucial for homeostasis, development and diseases. Here, we identify UVRAG, a Beclin1-binding autophagic factor, as a PI(3)P-binding protein that depends on PI(3)P for its ER localization. We further show that UVRAG interacts with RINT-1, and acts as an integral component of the RINT-1-containing ER tethering complex, which couples phosphoinositide metabolism to COPI-vesicle tethering. Displacement or knockdown of UVRAG profoundly disrupted COPI cargo transfer to the ER and Golgi integrity. Intriguingly, autophagy caused the dissociation of UVRAG from the ER tether, which in turn worked in concert with the Bif-1-Beclin-PI(3)KC3 complex to mobilize Atg9 translocation for autophagosome formation. These findings identify a regulatory mechanism that coordinates Golgi-ER retrograde and autophagy-related vesicular trafficking events through physical and functional interactions between UVRAG, phosphoinositide, and their regulatory factors, thereby ensuring spatiotemporal fidelity of membrane trafficking and maintenance of organelle homeostasis.