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

TY - JOUR

T1 - The GTPase Domain of MX2 Interacts with the HIV-1 Capsid, Enabling Its Short Isoform to Moderate Antiviral Restriction

AU - Betancor , Gilberto

AU - Dicks, Matthew D.J.

AU - Jimenez Guardeno, Jose M.

AU - Ali, Nabil H.

AU - Apolonia, Luis

AU - Malim, Michael H.

PY - 2019/11/12

Y1 - 2019/11/12

N2 - 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.

AB - 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.

KW - GTPase domain

KW - HIV-1

KW - MX2

KW - antiviral activity

KW - capsid

KW - protein isoform

UR - http://www.scopus.com/inward/record.url?scp=85074669272&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2019.10.009

DO - 10.1016/j.celrep.2019.10.009

M3 - Article

SN - 2211-1247

VL - 29

SP - 1923-1933.e3

JO - Cell Reports

JF - Cell Reports

IS - 7

ER -