Interferon‐Induced Mx Proteins: Dynamin‐Like GTPases with Antiviral Activity

Abstract

Mx proteins are interferon-induced GTPases that belong to the dynamin superfamily of large GTPases. Similarities include a high molecular weight, a propensity to self-assemble, a relatively low affinity for GTP, and a high intrinsic rate of GTP hydrolysis. A unique property of Mx GTPases is their antiviral activity against a wide range of RNA viruses, including bunyaand orthomyxoviruses. The human MxA GTPase accumulates in the cytoplasm of interferon-treated cells, partly associating with the endoplasmic reticulum. In the case of bunyaviruses, MxA interferes with transport of the viral nucleocapsid protein (N) to the Golgi compartment, the site of virus assembly. In the case of Thogoto virus (an orthomyxovirus), MxA prevents the incoming viral nucleocapsids from being transported into the nucleus, the site of viral transcription and replication. In both cases, the GTP-binding and carboxyterminal effector functions of MxA are required for target recognition. In general, Mx GTPases appear to detect viral infection by sensing nucleocapsid-like structures. As a consequence, these viral components are trapped and sorted to locations where they become unavailable for the generation of new virus particles.

Interferon-Induced Expression of MxA in the Respiratory Tract of Rhesus Macaques Is Suppressed by Influenza Virus Replication

“…These results suggest that, in mouse 3T3 cells, MxA interferes with either intracytoplasmic transport of viral mRNAs, viral protein synthesis, or translocation of newly synthesized viral proteins to the cell nucleus (33). More recent studies have shown that if MxA is artificially made to translocate into the nucleus of 3T3 cells, it binds newly synthesized influenza virus nucleoprotein, preventing viral transcription (4,31,33). There is only one report of MxA-mediated antiviral activity in human cells; it has been demonstrated that MxA inhibits cytoplasmic LaCrosse virus genome replication (34).…”

“…The human Mx homologue MxA is able to inhibit the replication of orthomyxoviruses and other RNA viruses (reviewed in Ref. 4). MxA expression and MxA-mediated resistance to the influenza virus is associated with IFN-␣␤-dependent, IFN-␣␤-stimulated response element (ISRE) induction (5), and MxA expression during influenza virus infection requires type I and type III IFN activity (5).…”

Intra- and Intermolecular Domain Interactions of the C-terminal GTPase Effector Domain of the Multimeric Dynamin-like GTPase Drp1

“…In dynamin, dimers/tetramers assemble to form rings and collars at the base of clathrin-coated pits, inducing cooperative increases in its GTPase activity (2)(3)(4)(5). Formation of higher order structures and cooperative increases in GTPase activity have also been described for the dynamin-related Mx and guanylate-binding protein families (17)(18)(19)(20). In many cases, detailed analyses have been performed to characterize the domains involved in assembly and cooperative GTPase stimulation of these proteins.…”

“…A common theme throughout the diverse dynamin superfamily is that self-assembly and oligomerization play important roles in the function of these proteins (1)(2)(3)(4)(5)17). In dynamin, dimers/tetramers assemble to form rings and collars at the base of clathrin-coated pits, inducing cooperative increases in its GTPase activity (2)(3)(4)(5).…”

Deducing Interactions in Partially Unspecified Biological Systems

“…This evolution, not considered in [8], mimics the presence of a Mxlike protein in the cell that inhibits the replication of the virus. This type of proteins seems to play an antiviral activity by trapping the viral capsid and moving it in a location of the cell where the mechanism for the generation of new virus particles becomes unavailable [18]. The simplest representation of the Mx protein can be drawn from…”