PtdIns(3)P-bound UVRAG coordinates Golgi-ER retrograde and Atg9 transport by differential interactions with the ER tether and the beclin 1 complex.
Endoplasmic reticulum (ER)-Golgi membrane transport and autophagy are intersecting trafficking pathways that are tightly regulated and crucial for homeostasis, development and disease. Here, we identify UVRAG, a beclin-1-binding autophagic factor, as a phosphatidylinositol-3-phosphate (PtdIns(3)P)-binding protein that depends on PtdIns(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-1-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.
Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA.
Shanshan
S
He
Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA.
Duojiao
D
Ni
Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA.
Binyun
B
Ma
Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA.
Joo-Hyung
JH
Lee
Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA.
Tian
T
Zhang
Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA.
Irene
I
Ghozalli
Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA.
Sara Dolatshahi
SD
Pirooz
Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA.
Zhen
Z
Zhao
Division of Structural Biology and Biochemistry, School of Biological Sciences, Nanyang Technological University, Singapore 637551.
Nagakumar
N
Bharatham
Division of Structural Biology and Biochemistry, School of Biological Sciences, Nanyang Technological University, Singapore 637551.
Baihong
B
Li
Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA.
Soohwan
S
Oh
Department of Biological Chemistry, University of California, Irvine, Irvine, California 92697.
Wen-Hwa
WH
Lee
Department of Pharmacology and Penn State Hershey Cancer Institute; The Pennsylvania State University College of Medicine; Hershey, PA USA.
Yoshinori
Y
Takahashi
Department of Pharmacology and Penn State Hershey Cancer Institute; The Pennsylvania State University College of Medicine; Hershey, PA USA.
Hong-Gang
HG
Wang
Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA.
Arlet
A
Minassian
Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA.
Pinghui
P
Feng
Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131.
Vojo
V
Deretic
European Molecular Biology Laboratory, Heidelberg, Cell Biology/Cell Biophysics Unit, Meyerhofstr. 1, D-69117 Heidelberg Germany.
Rainer
R
Pepperkok
School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0393, Japan.
Mitsuo
M
Tagaya
Division of Structural Biology and Biochemistry, School of Biological Sciences, Nanyang Technological University, Singapore 637551.|Department of Genetic Engineering, College of Life Sciences, Kyung Hee University, Yongin-si, Gyeonggi-do, 446-701, Republic of Korea.
Ho Sup
HS
Yoon
Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA.
Chengyu
C
Liang
D000595:Amino Acid Sequence; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D000071186:Beclin-1; D001692:Biological Transport; D019556:COS Cells; D002460:Cell Line; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010716:Phosphatidylinositols / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D033921:Vesicular Transport Proteins
D051017:Apoptosis Regulatory Proteins; C574794:ATG9A protein, human; D000071183:Autophagy-Related Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D010716:Phosphatidylinositols; D025521:Tumor Suppressor Proteins; C408122:UVRAG protein, human; D033921:Vesicular Transport Proteins