title: Kinesin KIF4 regulates intracellular trafficking and stability of the human immunodeficiency virus type 1 Gag polyprotein.
abstract: Retroviral Gag proteins are synthesized as soluble, myristoylated precursors that traffic to the plasma membrane and promote viral particle production. The intracellular transport of human immunodeficiency virus type 1 (HIV-1) Gag to the plasma membrane remains poorly understood, and cellular motor proteins responsible for Gag movement are not known. Here we show that disrupting the function of KIF4, a kinesin family member, slowed temporal progression of Gag through its trafficking intermediates and inhibited virus-like particle production. Knockdown of KIF4 also led to increased Gag degradation, resulting in reduced intracellular Gag protein levels; this phenotype was rescued by reintroduction of KIF4. When KIF4 function was blocked, Gag transiently accumulated in discrete, perinuclear, nonendocytic clusters that colocalized with endogenous KIF4, with Ubc9, an E2 SUMO-1 conjugating enzyme, and with SUMO. These studies identify a novel transit station through which Gag traffics en route to particle assembly and highlight the importance of KIF4 in regulating HIV-1 Gag trafficking and stability.
authors.affiliation: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 143, New York, NY 10065, USA.
authors.forename: Nathaniel W
authors.initials: NW
authors.lastname: Martinez
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Xue
authors.forename: Reem G
authors.initials: RG
authors.lastname: Berro
authors.forename: Geri
authors.initials: G
authors.lastname: Kreitzer
authors.forename: Marilyn D
authors.initials: MD
authors.lastname: Resh
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003593:Cytoplasm / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D025842:SUMO-1 Protein; D054301:gag Gene Products, Human Immunodeficiency Virus; D044763:Ubiquitin-Conjugating Enzymes; C484228:KIF4A protein, human; D016547:Kinesins; D000098843:Ubiquitin-Conjugating Enzyme UBC9