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

Yiping Zhu1, Shukun Luo2, Yosef Sabo1

  • 1Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biophysics, and Department of Microbiology and Immunology, Columbia University, New York, NY 10032, USA.

Cell Host & Microbe
|January 31, 2017
PubMed

Insights

Heme oxygenase-2 (HO-2) binds myristate on HIV-1 Gag, inhibiting virus replication and inflammation. HO-2 deficiency increases viral production and hyperactivates inflammatory signaling pathways.

Area of Science:

  • Biochemistry
  • Virology
  • Immunology

Background:

  • N-myristoylation is crucial for HIV-1 Gag protein function in virus budding.
  • Host factors interacting with HIV-1 matrix domain (MA) are key to understanding viral replication.
  • Cellular inflammatory responses are tightly regulated and involve complex signaling pathways.

Purpose of the Study:

  • To identify host factors binding to the N-myristoylated HIV-1 Gag matrix domain.
  • To elucidate the role of heme oxygenase-2 (HO-2) in HIV-1 replication and host inflammatory responses.
  • To investigate the mechanism by which HO-2 interacts with myristoylated proteins and regulates TLR4 signaling.

Main Methods:

  • Screening for host factors interacting with HIV-1 MA.
  • Co-immunoprecipitation and Western blotting to confirm protein interactions.
  • Crystal structure analysis of HO-2 binding to myristate.
  • Inhibition of HO-2 expression and myristate binding.
  • Assessment of HIV-1 replication and TLR4 signaling pathway activation.

Main Results:

  • Heme oxygenase-2 (HO-2) specifically binds the myristate moiety of HIV-1 Gag MA.
  • HO-2 also binds TRAM, an adaptor protein for Toll-like receptor 4 (TLR4).
  • Inhibiting HO-2 or its myristate binding significantly increased HIV-1 production.
  • HO-2 deficiency led to hyperresponsive TRAM-dependent TLR4 signaling and increased sensitivity to lipopolysaccharide.
  • Crystal structure showed HO-2 binds myristate in a hydrophobic channel.

Conclusions:

  • HO-2 is a cellular myristate-binding protein with a significant role in regulating HIV-1 replication.
  • HO-2 negatively impacts viral production by interacting with the myristoylated Gag protein.
  • HO-2 acts as a negative regulator of host inflammatory responses, particularly TRAM-dependent TLR4 signaling.
  • Targeting HO-2 or its myristate-binding function could offer new strategies for antiviral therapies and managing inflammatory conditions.
Keywords:
HIV-1MyristoylationTLR4TRAMheme oxygenase 2lipopolysaccharidemyristoyl-binding proteinretrovirus Gag

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