title: Heme Oxygenase 2 Binds Myristate to Regulate Retrovirus Assembly and TLR4 Signaling.
abstract: N-myristoylation is the covalent attachment of myristic acid to the N terminus of proteins in eukaryotic cells. The matrix domain (MA) of HIV-1 Gag protein is N-myristoylated and plays an important role in virus budding. In screening for host factors that interact with HIV-1 MA, we found that heme oxygenase (HO-2) specifically binds the myristate moiety of Gag. HO-2 was also found to bind TRAM, an adaptor protein for Toll-like receptor 4 (TLR4), and thereby impact both virus replication and cellular inflammatory responses. A crystal structure revealed that HO-2 binds myristate via a hydrophobic channel adjacent to the heme-binding pocket. Inhibiting HO-2 expression, or blocking myristate binding with a heme analog, led to marked increases in virus production. HO-2 deficiency caused hyperresponsive TRAM-dependent TLR4 signaling and hypersensitivity to the TLR4 ligand lipopolysaccharide. Thus, HO-2 is a cellular myristate-binding protein that negatively regulates both virus replication and host inflammatory responses.
authors.affiliation: Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biophysics, and Department of Microbiology and Immunology, Columbia University, New York, NY 10032, USA.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Shukun
authors.initials: S
authors.lastname: Luo
authors.affiliation: Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biophysics, and Department of Microbiology and Immunology, Columbia University, New York, NY 10032, USA.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Sabo
authors.affiliation: Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biophysics, and Department of Microbiology and Immunology, Columbia University, New York, NY 10032, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Tong
authors.affiliation: Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biophysics, and Department of Microbiology and Immunology, Columbia University, New York, NY 10032, USA.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Goff
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D054884:Host-Pathogen Interactions / Q000235:genetics; D006801:Humans; D008070:Lipopolysaccharides / Q000378:metabolism; D019814:Myristic Acid / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014771:Virion / Q000378:metabolism; D019065:Virus Assembly; D014779:Virus Replication; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008070:Lipopolysaccharides; C480228:TICAM2 protein, human; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D054301:gag Gene Products, Human Immunodeficiency Virus; D019814:Myristic Acid; D006419:Heme Oxygenase (Decyclizing); C105245:heme oxygenase-2
keywords: HIV-1; Myristoylation; TLR4; TRAM; heme oxygenase 2; lipopolysaccharide; myristoyl-binding protein; retrovirus Gag