The GTPase Domain of MX2 Interacts with the HIV-1 Capsid, Enabling Its Short Isoform to Moderate Antiviral Restriction

• DOI: 10.1016/j.celrep.2019.10.009
• Publication Date: 2019-11-12T15:53:45Z
• Authors: Gilberto Betancor; Matthew D.J. Dicks; Jose M. Jimenez-G...; Nabil H. Ali; Luis Apolonia; Michael H. Malim
• Keywords: Myxovirus Resistance Proteins; 0301 basic medicine; 570; QH301-705.5; 610; HIV Infections; Article; GTPase domain; Protein isoform; 03 medical and health sciences; Capsid; Protein Domains; capsid; Humans; Protein Isoforms; MX2; Biology (General); Antiviral activity; 0303 health sciences; protein isoform; 2407 Biología celular; 3. Good health; antiviral activity; HIV-1; 32 Ciencias médicas; HeLa Cells; Protein Binding

Myxovirus resistance 2 (MX2/MXB) is an interferon (IFN)-induced HIV-1 restriction factor that inhibits viral nuclear DNA accumulation. The amino-terminal domain of MX2 binds the viral capsid and is essential for inhibition. Using in vitro assembled Capsid-Nucleocapsid (CANC) complexes as a surrogate for the HIV-1 capsid lattice, we reveal that the GTPase (G) domain of MX2 contains a second, independent capsid-binding site. The importance of this interaction was addressed in competition assays using the naturally occurring non-antiviral short isoform of MX2 that lacks the amino-terminal 25 amino acids. Specifically, these experiments show that the G domain enhances MX2 function, and the foreshortened isoform acts as a functional suppressor of the full-length protein in a G-domain-dependent manner. The interaction of MX2 with its HIV-1 capsid substrate is therefore multi-faceted: there are dual points of contact that, together with protein oligomerization, contribute to the complexity of MX2 regulation.