Heme Oxygenase 2 Binds Myristate to Regulate Retrovirus Assembly and TLR4 Signaling.
Heme Oxygenase 2 Binds Myristate to Regulate Retrovirus Assembly and TLR4 Signaling.
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DOI：
10.1016/j.chom.2017.01.002
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发表时间：
2017-02-08
影响因子：
30.3
通讯作者：
Goff SP
中科院分区：
文献类型：
--
作者：
Zhu Y;Luo S;Sabo Y;Wang C;Tong L;Goff SP
N-肉豆蔻酰化是肉豆蔻酸与真核细胞中蛋白质的N-末端的共价连接。HIV-1 Gag蛋白的基质结构域（Matrix domain，MA）被N-豆蔻酰化，在病毒出芽过程中起重要作用。在筛选与HIV-1 MA相互作用的宿主因子时，我们发现血红素加氧酶2（HO-2）特异性结合Gag的肉豆蔻酸酯部分。还发现HO-2结合TRAM，Toll样受体4（TLR 4）的衔接蛋白，从而影响病毒复制和细胞炎症反应。晶体结构显示HO-2通过邻近血红素结合口袋的疏水通道结合肉豆蔻酸。抑制HO-2的表达，或阻断肉豆蔻酸与血红素类似物的结合，导致病毒产量显着增加。HO-2缺乏引起高反应性TRAM依赖性TLR 4信号传导，和对TLR 4配体脂多糖的超敏反应。因此，HO-2是一种细胞肉豆蔻酸酯结合蛋白，负调节病毒复制和宿主炎症反应。
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 2 (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 analogue, 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.