title: Interferon-induced SCYL2 limits release of HIV-1 by triggering PP2A-mediated dephosphorylation of the viral protein Vpu.
abstract: Human cells respond to infection by retroviruses through the actions of proteins that inhibit the spread of viruses to other cells. One example is bone marrow stromal cell antigen 2 (BST2; also known as tetherin), which is an interferon (IFN)-inducible protein that restricts the release of progeny virions from infected cells. The HIV-1 accessory protein Vpu (viral protein U) causes degradation of BST2, and phosphorylation of Vpu at residues Ser(52) and Ser(56) is required for this function. We report that the host protein SCY1-like protein 2 (SCYL2) mediates the dephosphorylation of Vpu, antagonizing Vpu function and facilitating BST2-dependent restriction of HIV-1 release. SCYL2 reduced the number of virus particles released from cells infected with wild-type HIV-1, but not a strain lacking vpu, in a BST2-dependent manner. SCYL2 stimulated the dephosphorylation of Vpu on Ser(52) and Ser(56) by recruiting protein phosphatase 2A (PP2A) to Vpu. Conversely, depletion of SCYL2 resulted in enhanced phosphorylation of Vpu and increased viral particle release. Moreover, SCYL2 was produced in response to type I IFN and contributed to IFN-mediated viral restriction. Together, these results suggest that SCYL2 serves as a regulatory factor for Vpu, reducing the extent of Vpu phosphorylation and consequently enhancing BST2-mediated viral restriction.
authors.affiliation: Department of Microbiology, Yokohama City University School of Medicine, Kanagawa 236-0004, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Miyakawa
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Sawasaki
authors.forename: Satoko
authors.initials: S
authors.lastname: Matsunaga
authors.forename: Andrey
authors.initials: A
authors.lastname: Tokarev
authors.forename: Gary
authors.initials: G
authors.lastname: Quinn
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kimura
authors.forename: Masako
authors.initials: M
authors.lastname: Nomaguchi
authors.forename: Akio
authors.initials: A
authors.lastname: Adachi
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: John
authors.initials: J
authors.lastname: Guatelli
authors.forename: Akihide
authors.initials: A
authors.lastname: Ryo
mesh_terms: D002966:Clathrin / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology*; D054298:Human Immunodeficiency Virus Proteins / Q000378:metabolism*; D006801:Humans; D007372:Interferons / Q000502:physiology*; D010766:Phosphorylation; D011485:Protein Binding; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis*; D054334:Viral Regulatory and Accessory Proteins / Q000378:metabolism*; D014771:Virion / Q000378:metabolism; D000086082:Viroporin Proteins
chemical_list: D002966:Clathrin; D054298:Human Immunodeficiency Virus Proteins; D007372:Interferons; D054648:Protein Phosphatase 2; D017346:Protein Serine-Threonine Kinases; D054334:Viral Regulatory and Accessory Proteins; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins; C501863:SCYL2 protein, human