- Recommended name:
- Interferon-induced GTP-binding protein Mx1
This gene encodes a guanosine triphosphate (GTP)-metabolizing protein that participates in the cellular antiviral response. The encoded protein is induced by type I and type II interferons and antagonizes the replication process of several different RNA and DNA viruses. There is a related gene located adjacent to this gene on chromosome 21, and there are multiple pseudogenes located in a cluster on chromosome 4. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013] Its target viruses include negative-stranded RNA viruses and HBV through binding and inactivation of their ribonucleocapsid. May also antagonize reoviridae and asfarviridae replication. Inhibits thogoto virus (THOV) replication by preventing the nuclear import of viral nucleocapsids. Inhibits La Crosse virus (LACV) replication by sequestering viral nucleoprotein in perinuclear complexes, preventing genome amplification, budding, and egress. Inhibits influenza A virus (IAV) replication by decreasing or delaying NP synthesis and by blocking endocytic traffic of incoming virus particles. Enhances ER stress-mediated cell death after influenza virus infection. May regulate the calcium channel activity of TRPCs.
Aliases for MX1 Gene
- MX Dynamin Like GTPase 1 2 3 5
- Interferon-Regulated Resistance GTP-Binding Protein MxA 3 4
- Interferon-Induced GTP-Binding Protein Mx1 3 4
- Interferon-Inducible Protein P78 2 3
- Interferon-Induced Protein P78 3 4
- Myxoma Resistance Protein 1 3 4
- IFI-78K 3
- Myxovirus (Influenza) Resistance 1, Homolog Of Murine (Interferon-Inducible Protein P78) 2
- Myxovirus (Influenza Virus) Resistance 1, Interferon-Inducible Protein P78 (Mouse) 2
- Myxovirus (Influenza Virus) Resistance 1, Interferon-Inducible Protein P78 3
- Myxovirus Resistance Protein 1 4
- IFI78 3
- MxA 3
- MX
MxA Interacts With and Is Modified by the SUMOylation Machinery
Abstract
Mx proteins are evolutionarily conserved dynamin-like large
GTPases involved in viral resistance triggered by types I and III
interferons. The human MxA is a cytoplasmic protein that confers
resistance to a large number of viruses. The MxA protein is also known
to self-assembly into high molecular weight homo-oligomers. Using a
yeast two-hybrid screen, we identified 27 MxA binding partners, some of
which are related to the SUMOylation machinery. The interaction of MxA
with Small-Ubiquitin MOdifier 1 (SUMO1) and Ubiquitin conjugating enzyme
9 (Ubc9) was confirmed by co-immunoprecipitation and co-localization by
confocal microscopy. We identified one SUMO conjugation site at lysine
48 and two putative SUMO interacting motifs (SIMa and SIMb). We showed
that MxA interacts with the EIL loop of SUMO1 in a SIM-independent
manner via its CID-GED domain. The yeast two-hybrid mapping also
revealed that Ubc9 binds to the MxA GTPase domain. Mutation in the
putative SIMa and SIMb, which are located in the GTPase binding domain,
reduced MxA antiviral activity. In addition, we showed that MxA can be
conjugated to SUMO2 or SUMO3 at lysine 48 and that the
SUMOylation-deficient mutant of MxA (MxAK48R) retained its capacity to
oligomerize and to inhibit Vesicular Stomatitis Virus (VSV) and
Influenza A Virus replication, suggesting that MxA SUMOylation is not
essential for its antiviral activity.
Keywords:
EIL loop; MX1; MxA; SUMO; SUMOylation; Ubc9 and antiviral activity; Yeast two-hybrid.
Copyright © 2014 Elsevier Inc. All rights reserved.
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Mx proteins: GTPases involved in the interferon-induced antiviral state.Ciba Found Symp. 1993;176:233-43; discussion 243-7. doi: 10.1002/9780470514450.ch15. PMID: 7507812 Review.Abstract. Mx proteins have molecular masses between 70 and 80 kDa and their synthesis is tightly regulated by interferons in mammalian and non-mammalian vertebrates. Some Mx proteins function as intracellular mediators of the interferon-induced antiviral state. When suitable cDNA constructs were constitutively expressed in mouse 3T3 cells the mouse nuclear Mx1 protein conferred selective resistance to influenza virus. The human cytoplasmic MxA protein conferred resistance to influenza virus and vesicular stomatitis virus but not to other viruses. Mx1 blocks influenza virus mRNA synthesis within the nucleus of infected cells. Mx1 presumably interacts with the influenza virus polymerase subunit PB2, because overexpression of PB2 titrates out the Mx1 block. MxA does not inhibit mRNA synthesis of influenza virus; it inhibits a subsequent cytoplasmic viral multiplication step. A possible target is the transport of newly synthesized influenza virus polymerase proteins back to the nucleus. Inhibition by MxA of vesicular stomatitis virus, which replicates in the cytoplasm, is at the transcriptional level. Parts of the N-terminal halves of all known Mx proteins are highly conserved. They contain the typical GTP-binding motif and show significant homology to other members of a new family of GTPases that includes rat dynamin, Drosophila Shibire and the yeast proteins Vps1/Spo15 and Mgm1. Purified Mx1 and MxA proteins possess GTPase activity. The GTP/GDP conversion rates are about 40 per min, and Km values about 700 microM. Mx1 and MxA variants with mutations in the GTP-binding sequences that violate the consensus are unable to confer virus resistance in vivo or to hydrolyse GTP in vitro, suggesting that GTPase activity is necessary for antiviral activity of Mx proteins. We hypothesize that the antivirally active Mx proteins (directly or indirectly) bind to polymerase proteins of susceptible viruses, thereby abolishing normal viral polymerase function. Interaction of Mx with viral targets is probably a GTP-dependent process.
Human MxA Is a Potent Interspecies Barrier for the Novel Bat-Derived Influenza A-like Virus H18N11
Affiliations
Free PMC article
Abstract
The human innate immune factor MxA represents an effective
interspecies barrier for zoonotic influenza A viruses (IAVs) of animal
origin. Accordingly, human but not avian IAVs efficiently escape the
antiviral activity of MxA due to adaptive mutations in their viral
nucleoprotein. Partial MxA resistance can be acquired in intermediate
hosts such as swine, which possess an antivirally active Mx1 protein.
Intriguingly, Mx1 of the bat Carollia perspicillata, a host of the
recently discovered bat influenza A-like virus H18N11, is antivirally
active against avian IAVs, thus raising the question whether H18N11 has
undergone a preadaptation to human MxA. Here, by utilizing a chimeric
bat influenza virus, PR8-H18N11, we demonstrate that MxA efficiently
blocks viral replication in vitro as well as in MxA transgenic mice.
Nevertheless, the H18N11 nucleoprotein exhibits partial MxA resistance
in a polymerase reconstitution assay, suggesting that a certain degree
of MxA preadaptation occurred. Together, our data indicate a currently
reduced risk for H18N11 to overcome the human restriction factor MxA.
Further adaptive mutations in NP are required to facilitate full MxA
escape.
Keywords:
Bat influenza A virus; H18N11; MxA; PR8-H18N11; chimeric influenza A virus; interspecies barrier; zoonotic spill-over.
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