title: TANK-binding kinase 1 attenuates PTAP-dependent retroviral budding through targeting endosomal sorting complex required for transport-I.
abstract: Retroviruses need to bud from producer cells to spread infection. To facilitate its budding, some virus hijacks the multivesicular body (MVB) pathway that is normally used to cargo and degrade ubiquitylated cellular proteins, through interaction between the late domain of Gag polyproteins and the components of MVB machinery. In this study, we demonstrated that TANK-binding kinase 1 (TBK1) directly interacted with VPS37C, a subunit of endosomal sorting complex required for transport-I (ESCRT-I) in the MVB pathway, without affecting the ultrastructure or general function of MVB. Interestingly, overexpression of TBK1 attenuated, whereas short hairpin RNA interference of TBK1 enhanced HIV-1 pseudovirus release from Vero cells in type I IFN (IFN-I)-independent manner. Down-regulation of TBK1 by short hairpin RNA in TZM-bl cells also enhanced live HIV-1 NL4-3 or JR-CSF virus budding without involvement of IFN-I induction. Furthermore, infection of TBK1-deficient mouse embryonic fibroblast cells with a chimeric murine leukemia virus/p6, whose PPPY motif was replaced by PTAP motif of HIV-1, showed that lack of TBK1 significantly enhanced PTAP-dependent, but not PPPY-dependent retrovirus budding. Finally, phosphorylation of VPS37C by TBK1 might regulate the viral budding efficiency, because overexpression of the kinase-inactive mutant of TBK1 (TBK1-K38A) in Vero cells accelerated HIV-1 pseudovirus budding. Therefore, through tethering to VPS37C of the ESCRT-I complex, TBK1 controlled the speed of PTAP-dependent retroviral budding through phosphorylation of VPS37C, which would serve as a novel mechanism of host cell defense independent of IFN-I signaling.
authors.affiliation: Key Laboratory of Infection and Immunity, Chinese Academy of Sciences, Institute of Biophysics, Beijing, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Da
authors.forename: Xuanming
authors.initials: X
authors.lastname: Yang
authors.forename: Youli
authors.initials: Y
authors.lastname: Xu
authors.forename: Guangxia
authors.initials: G
authors.lastname: Gao
authors.forename: Genhong
authors.initials: G
authors.lastname: Cheng
authors.forename: Hong
authors.initials: H
authors.lastname: Tang
mesh_terms: D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D057809:HEK293 Cells; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D009052:Leukemia Virus, Murine / Q000254:growth & development / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D057146:Multivesicular Bodies / Q000502:physiology / Q000648:ultrastructure / Q000821:virology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D012192:Retroviridae Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology; D015398:Signal Transduction / Q000276:immunology; D014412:Tumor Virus Infections / Q000276:immunology / Q000378:metabolism; D014709:Vero Cells; D014779:Virus Replication / Q000276:immunology*
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human