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: Yiping Zhu, Shukun Luo, Yosef Sabo, Cheng Wang, Liang Tong, Stephen P Goff
• Journal: Cell host & microbe (Cell Host Microbe) Vol. 21 Issue 2 Pg. 220-230 (Feb 08 2017) ISSN: 1934-6069 [Electronic] United States
• PMID: 28132836 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Adaptor Proteins, Signal Transducing
• Lipopolysaccharides
• TICAM2 protein, human
• TLR4 protein, human
• Toll-Like Receptor 4
• gag Gene Products, Human Immunodeficiency Virus
• Myristic Acid
• Heme Oxygenase (Decyclizing)
• heme oxygenase-2

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• HEK293 Cells
• HIV-1 (genetics, physiology)
• Heme Oxygenase (Decyclizing) (genetics, metabolism)
• Host-Pathogen Interactions (genetics)
• Humans
• Lipopolysaccharides (metabolism)
• Myristic Acid (metabolism)
• Signal Transduction
• Toll-Like Receptor 4 (genetics, metabolism)
• Virion (metabolism)
• Virus Assembly
• Virus Replication
• gag Gene Products, Human Immunodeficiency Virus (genetics, metabolism)