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Heme Oxygenase 2 Binds Myristate to Regulate Retrovirus Assembly and TLR4 Signaling.

Heme Oxygenase 2 Binds Myristate to Regulate Retrovirus Assembly and TLR4 Signaling.
Author Information (click to view)

Zhu Y, Luo S, Sabo Y, Wang C, Tong L, Goff SP,


Zhu Y, Luo S, Sabo Y, Wang C, Tong L, Goff SP, (click to view)

Zhu Y, Luo S, Sabo Y, Wang C, Tong L, Goff SP,

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Cell host & microbe 2017 01 2621(2) 220-230 pii 10.1016/j.chom.2017.01.002

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.

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