title: Huwe1, a novel cellular interactor of Gag-Pol through integrase binding, negatively influences HIV-1 infectivity.
abstract: Integration, an indispensable step for retrovirus replication, is executed by integrase (IN), which is expressed as a part of a Gag-Pol precursor. Although mechanistic detail of the IN-catalyzed integration reaction is well defined, numerous evidence have demonstrated that IN is involved in multiple steps of retrovirus replication other than integration. In this study, Huwe1, a HECT-type E3 ubiquitin ligase, was identified as a new cellular interactor of human immunodeficiency virus type 1 (HIV-1) IN. The interaction was mediated through the catalytic core domain of IN and a wide-range region of Huwe1. Interestingly, although depletion of Huwe1 in target cells did not affect the early phase of HIV-1 infection in a human T cell line, we found that infectivity of HIV-1 released from the Huwe1 knockdown cells was significantly augmented more than that of virus produced from control cells. The increase in infectivity occurred in proviral DNA synthesis. Further analysis revealed that Huwe1 interacted with HIV-1 Gag-Pol precursor protein through an IN domain. Our results suggest that Huwe1 in HIV-1 producer cells has a negative impact on early post-entry events during the next round of virus infection via association with an IN region of Gag-Pol.
authors.affiliation: Laboratory of Viral Pathogenesis, Institute for Virus Research, Kyoto University, 53 Shogoin-kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Seiji P
authors.initials: SP
authors.lastname: Yamamoto
authors.forename: Katsuya
authors.initials: K
authors.lastname: Okawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakano
authors.forename: Kouichi
authors.initials: K
authors.lastname: Sano
authors.forename: Kanako
authors.initials: K
authors.lastname: Ogawa
authors.forename: Takao
authors.initials: T
authors.lastname: Masuda
authors.forename: Yuko
authors.initials: Y
authors.lastname: Morikawa
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Koyanagi
authors.forename: Youichi
authors.initials: Y
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D002460:Cell Line; D015685:Fusion Proteins, gag-pol / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D015658:HIV Infections / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity* / Q000648:ultrastructure; D006367:HeLa Cells; D006801:Humans; D019426:Integrases / Q000378:metabolism*; D051379:Mice; D008979:Moloney murine leukemia virus / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D015685:Fusion Proteins, gag-pol; D025521:Tumor Suppressor Proteins; C502830:HUWE1 protein, human; D044767:Ubiquitin-Protein Ligases; D019426:Integrases