Antivirally active MxA protein sequesters La Crosse virus nucleocapsid protein into perinuclear complexes

Kochs, Georg; Janzen, Christian J.; Hohenberg, Heinz; Haller, Otto

doi:10.1073/pnas.052430399

Cited by 192 publications

(194 citation statements)

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“…In general, nuclear Mx proteins (e.g., mouse Mx1) protect against viruses that replicate in the nucleus, such as influenza virus and Thogoto virus (THOV) (2-10), whereas cytoplasmic forms (e.g., mouse Mx2) inhibit replication of vesicular stomatitis virus (VSV) and other viruses that replicate in the cytoplasm (11)(12)(13). The human MxA protein is cytoplasmic and has a broad antiviral spectrum that is seemingly unrelated to the intracellular replication site of the virus (5,(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Antiviral activity has also been described for fish Mx proteins (31)(32)(33)(34)(35)(36)(37).…”

Section: Introductionmentioning

confidence: 99%

Mx Proteins: Antiviral Gatekeepers That Restrain the Uninvited

Verhelst

Hulpiau

Saelens

2013

Microbiol Mol Biol Rev

255

178

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SUMMARY Fifty years after the discovery of the mouse Mx1 gene, researchers are still trying to understand the molecular details of the antiviral mechanisms mediated by Mx proteins. Mx proteins are evolutionarily conserved dynamin-like large GTPases, and GTPase activity is required for their antiviral activity. The expression of Mx genes is controlled by type I and type III interferons. A phylogenetic analysis revealed that Mx genes are present in almost all vertebrates, usually in one to three copies. Mx proteins are best known for inhibiting negative-stranded RNA viruses, but they also inhibit other virus families. Recent structural analyses provide hints about the antiviral mechanisms of Mx proteins, but it is not known how they can suppress such a wide variety of viruses lacking an obvious common molecular pattern. Perhaps they interact with a (partially) symmetrical invading oligomeric structure, such as a viral ribonucleoprotein complex. Such an interaction may be of a fairly low affinity, in line with the broad target specificity of Mx proteins, yet it would be strong enough to instigate Mx oligomerization and ring assembly. Such a model is compatible with the broad “substrate” specificity of Mx proteins: depending on the size of the invading viral ribonucleoprotein complexes that need to be wrapped, the assembly process would consume the necessary amount of Mx precursor molecules. These Mx ring structures might then act as energy-consuming wrenches to disassemble the viral target structure.

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Section: Introductionmentioning

confidence: 99%

Mx Proteins: Antiviral Gatekeepers That Restrain the Uninvited

Verhelst

Hulpiau

Saelens

2013

Microbiol Mol Biol Rev

255

178

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“…The viral target of MxA antiviral activity against orthomyxo-and bunyaviruses is the nucleoprotein, a component of viral nucleocapsids which encapsidates the viral negative strand RNA genome (13,14). In bunyavirus-infected cells, MxA binds and relocates the viral nucleoprotein (N) into perinuclear complexes associated with the smooth endoplasmic reticulum.…”

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confidence: 99%

“…In bunyavirus-infected cells, MxA binds and relocates the viral nucleoprotein (N) into perinuclear complexes associated with the smooth endoplasmic reticulum. This sequestration of N is thought to inhibit viral replication (13,15). MxA also interacts with the nucleoprotein (NP) of Thogoto virus (THOV), a tick-borne orthomyxovirus, thereby blocking the nuclear import of THOV nucleocapsids and consequently viral replication (16,17).…”

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confidence: 99%

Effects of allelic variations in the human myxovirus resistance protein A on its antiviral activity

Graf

Dick

Sendker

et al. 2018

Journal of Biological Chemistry

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Only a minority of patients infected with seasonal influenza A viruses exhibits a severe or fatal outcome of infection, but the reasons for this inter-individual variability in influenza susceptibility are unclear. To gain further insights into the molecular mechanisms underlying this variability, we investigated naturally occurring allelic variations of the myxovirus resistance 1 (MX1) gene coding for the influenza restriction factor MxA. The interferon-induced dynamin-like GTPase consists of an N-terminal GTPase domain, a bundle signaling element, and a C-terminal stalk responsible for oligomerization and viral target recognition. We used online databases to search for variations in the MX1 gene. Deploying in vitro approaches, we found that non-synonymous variations in the GTPase domain cause the loss of antiviral and enzymatic activities. Furthermore, we showed that these amino acid substitutions disrupt the interface for GTPase domain dimerization required for the stimulation of GTP hydrolysis. Variations in the stalk were neutral or slightly enhanced or abolished MxA antiviral function.http://www.jbc.org/cgi

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“…The most studied dynamin-like protein that exhibits antiviral activity is MxA (1,2). Contrary to MxB, the antiviral role of MxA has been extensively studied for viruses including influenza virus (1,(12)(13)(14)(15), tick-borne Thogoto virus (16), African swine fever virus (17), hepatitis B virus (18), and La Crosse virus (19,20). The antiviral activity of the long form of MxB was recently described (9,(21)(22)(23); these investigations led to the discovery that the IFN-␣-inducible protein MxB blocks HIV-1 infection.…”

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confidence: 99%

MxB Is Not Responsible for the Blocking of HIV-1 Infection Observed in Alpha Interferon-Treated Cells

Opp

Vieira

Schulte

et al. 2016

J Virol

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MxB restricts HIV-1 infection by directly interacting with the HIV-1 core, which is made of viral capsid; however, the contribution of MxB to the HIV-1 restriction observed in alpha interferon (IFN-␣)-treated human cells is unknown. To understand this contribution, we used HIV-1 bearing the G208R capsid mutant (HIV-1-G208R), which overcomes the restriction imposed by cells expressing MxB. Here we showed that the reason why MxB does not block HIV-1-G208R is that MxB does not interact with HIV-1 cores bearing the mutation G208R. M yxovirus resistance proteins represent a family of interferon-inducible factors with a wide range of antiviral activities (1-3). The myxovirus B (MxB) gene was originally cloned from a human glioblastoma cell line treated with alpha interferon (IFN-␣) (4, 5). MxB as well as the related protein MxA belong to the dynamin-like family of proteins, which have diverse functions ranging from vesicle transport to antiviral activity (1, 6-11). The most studied dynamin-like protein that exhibits antiviral activity is MxA (1, 2). Contrary to MxB, the antiviral role of MxA has been extensively studied for viruses including influenza virus (1, 12-15), tick-borne Thogoto virus (16), African swine fever virus (17), hepatitis B virus (18), and La Crosse virus (19,20). The antiviral activity of the long form of MxB was recently described (9, 21-23); these investigations led to the discovery that the IFN-␣-inducible protein MxB blocks HIV-1 infection.Genetic evidence suggested that the HIV-1 capsid is the determinant for the ability of MxB to block HIV-1 infection (9,22,23). In agreement with these findings, we recently demonstrated that MxB binds to the HIV-1 capsid and correlated the ability of MxB to block HIV-1 infection with inhibition of uncoating (24). We also showed that the ability of MxB to block infection requires a capsid binding domain and an oligomerization domain provided by the 90 N-terminal and the 143 C-terminal amino acids of MxB, respectively (24). In addition, the work of others and our work showed that the 90 N-terminal amino acids of MxB are important for its ability to bind capsid and restrict HIV-1 infection (24)(25)(26).MxB contains a previously described putative nuclear localization signal on its N-terminal 25 amino acids (4). Deletion of the N-terminal 25 amino acids annihilates the ability of MxB to block HIV-1 infection and to bind to the HIV-1 core (23,24,27). Mutagenic studies have revealed that the N-terminal 25 amino acids of MxB exhibit a triple-arginine motif ( 11 RRR 13 ) that is important for restriction and the ability of MxB to bind to the HIV-1 core (28, 29). HIV-1 CA-NC expression and purification. The CA-NC proteins of HIV-1 and HIV-1 bearing the G208R capsid mutant (HIV-1-G208R) were expressed, purified, and assembled as previously described (30). MATERIALS AND METHODS CellMxB binding to in vitro-assembled HIV-1 and HIV-1-G208R CA-NC complexes. HEK 293T cells were transfected with a plasmid expressing the wild-type MxB protein. Forty-eight hours after t...

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Antivirally active MxA protein sequesters La Crosse virus nucleocapsid protein into perinuclear complexes

Cited by 192 publications

References 40 publications

Mx Proteins: Antiviral Gatekeepers That Restrain the Uninvited

Mx Proteins: Antiviral Gatekeepers That Restrain the Uninvited

Effects of allelic variations in the human myxovirus resistance protein A on its antiviral activity

MxB Is Not Responsible for the Blocking of HIV-1 Infection Observed in Alpha Interferon-Treated Cells

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