Structural basis of HIV-1 Vpu-mediated BST2 antagonism via hijacking of the clathrin adaptor protein complex 1.
BST2/tetherin, an antiviral restriction factor, inhibits the release of enveloped viruses from the cell surface. Human immunodeficiency virus-1 (HIV-1) antagonizes BST2 through viral protein u (Vpu), which downregulates BST2 from the cell surface. We report the crystal structure of a protein complex containing Vpu and BST2 cytoplasmic domains and the core of the clathrin adaptor protein complex 1 (AP1). This, together with our biochemical and functional validations, reveals how Vpu hijacks the AP1-dependent membrane trafficking pathways to mistraffick BST2. Vpu mimics a canonical acidic dileucine-sorting motif to bind AP1 in the cytosol, while simultaneously interacting with BST2 in the membrane. These interactions enable Vpu to build on an intrinsic interaction between BST2 and AP1, presumably causing the observed retention of BST2 in juxtanuclear endosomes and stimulating its degradation in lysosomes. The ability of Vpu to hijack AP-dependent trafficking pathways suggests a potential common theme for Vpu-mediated downregulation of host proteins.DOI: http://dx.doi.org/10.7554/eLife.02362.001.
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States.
Xiaofei
X
Jia
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States.
Erin
E
Weber
Department of Medicine, University of California San Diego, La Jolla, United States The VA San Diego Healthcare System, San Diego, United States.
Andrey
A
Tokarev
Department of Medicine, University of California San Diego, La Jolla, United States The VA San Diego Healthcare System, San Diego, United States.
Mary
M
Lewinski
Department of Medicine, University of California San Diego, La Jolla, United States The VA San Diego Healthcare System, San Diego, United States.
Maryan
M
Rizk
Department of Medicine, University of California San Diego, La Jolla, United States The VA San Diego Healthcare System, San Diego, United States.
Marissa
M
Suarez
Department of Medicine, University of California San Diego, La Jolla, United States The VA San Diego Healthcare System, San Diego, United States jguatelli@ucsd.edu.
John
J
Guatelli
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States yong.xiong@yale.edu.
Yong
Y
Xiong
D033961:Adaptor Protein Complex 1 / Q000235:genetics* / Q000378:metabolism; D033962:Adaptor Protein Complex 2 / Q000235:genetics / Q000378:metabolism; D033963:Adaptor Protein Complex 3 / Q000235:genetics / Q000378:metabolism; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002966:Clathrin / Q000235:genetics* / Q000378:metabolism; D003001:Cloning, Molecular; D003460:Crystallization; D015536:Down-Regulation; D011992:Endosomes / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D015497:HIV-1 / Q000235:genetics*; D006367:HeLa Cells; D054298:Human Immunodeficiency Virus Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D010766:Phosphorylation; D011487:Protein Conformation; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics* / Q000378:metabolism; D057074:Virus Release; D000074010:Bone Marrow Stromal Antigen 2; D000086082:Viroporin Proteins
D033961:Adaptor Protein Complex 1; D033962:Adaptor Protein Complex 2; D033963:Adaptor Protein Complex 3; D015703:Antigens, CD; D002966:Clathrin; D058851:GPI-Linked Proteins; D054298:Human Immunodeficiency Virus Proteins; D054334:Viral Regulatory and Accessory Proteins; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins
AP1; BST2; HIV; membrane trafficking; tetherin; vpu