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

Publication date: Available online 26 January 2017
Source:Cell Host & Microbe
Author(s): Yiping Zhu, Shukun Luo, Yosef Sabo, Cheng Wang, Liang Tong, Stephen P. Goff
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.

Graphical abstract

Teaser

Zhu et al. identify heme oxygenase 2 (HO-2) as a myristate-binding protein that interacts with an array of myristoylated proteins to negatively regulate their function. HO-2 binds HIV-1 Gag, which inhibits virion production, and TRAM, a key molecule in the LPS-TLR4 signaling pathway, to downregulate inflammatory responses.


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