title: Differential effects of human immunodeficiency virus type 1 Vpu on the stability of BST-2/tetherin.
abstract: BST-2/CD317/tetherin is a host factor that inhibits the release of HIV-1 and other unrelated viruses. A current model proposes that BST-2 physically tethers virions to the surface of virus-producing cells. The HIV-1-encoded Vpu protein effectively antagonizes the activity of BST-2. How Vpu accomplishes this task remains unclear; however, it is known that Vpu has the ability to down-modulate BST-2 from the cell surface. Here we analyzed the effects of Vpu on BST-2 by performing a series of kinetic studies with HeLa, 293T, and CEMx174 cells. Our results indicate that the surface downregulation of BST-2 is not due to an accelerated internalization or reduced recycling of internalized BST-2 but instead is caused by interference with the resupply of newly synthesized BST-2 from within the cell. While our data confirm previous reports that the high-level expression of Vpu can cause the endoplasmic reticulum (ER)-associated degradation of BST-2, we found no evidence that Vpu targets endogenous BST-2 in the ER in the course of a viral infection. Instead, we found that Vpu acts in a post-ER compartment and increases the turnover of newly synthesized mature BST-2. Our observation that Vpu does not affect the recycling of BST-2 suggests that Vpu does not act directly at the cell surface but may interfere with the trafficking of newly synthesized BST-2 to the cell surface, resulting in the accelerated targeting of BST-2 to the lysosomal compartment for degradation.
authors.affiliation: Viral Biochemistry Section, Laboratory of Molecular Microbiology, NIAID, NIH, Bldg. 4, Room 310, 4 Center Drive, MSC 0460, Bethesda, MD 20892-0460, USA.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Andrew
authors.forename: Eri
authors.initials: E
authors.lastname: Miyagi
authors.forename: Klaus
authors.initials: K
authors.lastname: Strebel
mesh_terms: D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D015536:Down-Regulation; D058851:GPI-Linked Proteins / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression; D015497:HIV-1 / Q000276:immunology* / Q000472:pathogenicity*; D054298:Human Immunodeficiency Virus Proteins / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D021381:Protein Transport; D054334:Viral Regulatory and Accessory Proteins / Q000276:immunology / Q000378:metabolism*; D000074010:Bone Marrow Stromal Antigen 2; D000086082:Viroporin Proteins
chemical_list: D015703:Antigens, CD; 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