Type I interferon (IFN) inhibits a wide spectrum of viruses through stimulating the expression of antiviral proteins. As an IFN-induced protein, myxovirus resistance B (MXB) protein was reported to inhibit multiple highly pathogenic human viruses. It remains to be determined whether MXB employs a common mechanism to restrict different viruses. Here, we find that IFN alters the subcellular localization of hundreds of host proteins, and this IFN effect is partially lost upon MXB depletion. The results of our mechanistic study reveal that MXB recognizes vimentin (VIM) and recruits protein kinase B (AKT) to phosphorylate VIM at amino acid S38, which leads to reorganization of the VIM network and impairment of intracellular trafficking of virus protein complexes, hence causing a restriction of virus infection. These results highlight a new function of MXB in modulating VIM-mediated trafficking, which may lead towards a novel broad-spectrum antiviral strategy to control a large group of viruses that depend on VIM for successful replication.

Herpesviruses present a major global disease burden. Understanding the host cell mechanisms that block viral infections, as well as how viruses can evolve to counteract these host defenses, is critically important for understanding viral disease pathogenesis. This study reveals that the major human variant of the antiviral protein myxovirus resistance protein B (MxB) inhibits the human pathogen herpes simplex virus (HSV-1), whereas a minor human variant and orthologous MxB genes from even closely related primates do not. Thus, in contrast to the many antagonistic virus-host interactions in which the virus is successful in thwarting the host\'s defense systems, here the human gene appears to be at least temporarily winning at this interface of the primate-herpesvirus evolutionary arms race. Our findings further show that a polymorphism at amino acid 83 in a small fraction of the human population is sufficient to abrogate MxB\'s ability to inhibit HSV-1, which could have important implications for human susceptibility to HSV-1 pathogenesis.

Hepatitis C virus (HCV) infection was the primary reason causing critical hepatic Q7 diseases. Although direct-acting antiviral agents (DAA) were widely used in clinics, anti-drug mutation, the outcome of patients with different viral subtypes, and recurrence suggested that HCV pathogenic mechanism should be studied further. HCV infection, replication, and outcome were influenced by the IFNL4 and itsdownstream genes (MxA and MxB). However, whether genetic polymorphisms of these genes played necessary roles required verification in the Yunnan population.
After analyzing the genotypes and allele frequencies of seven single nucleotide polymorphisms (SNP), we found the association between the genotype and allele frequencies of rs11322783 in the IFNL4 gene and HCV infection in Yunnan population. Furthermore, the genetic polymorphisms of the MxA and MxB genescould influence liver function of HCV patients. The indirect bilirubin (IBIL) and albumin (ALB) levels showed significant differences among HCV patients, who carried various genotypes. The IBIL levels were associated with genotypes of rs17000900 (P= 0.025) and rs2071430 (P= 0.037) in the MxA gene, and ALB levels were associated with genotypes of rs2838029 (P= 0.010) in the MxB gene. Similarly, the genotypes of SNPs also showed significant difference in patients infected with subtype 3a (P=0.035) and 2a (P=0.034). However, no association was identified between expression level and SNPs of the MxA and MxB genes. Furthermore, HCV subtype 3b was found to be the predominantly epidemic strain in Yunnan Province.
In conclusion, the association between biochemical indices/HCV subtypes and SNPs in the MxA and MxB genes was identified in Yunnan HCV population.

A restriction factor induced by interferons blocks the replication of herpesviruses by disassembling the capsid proteins surrounding their genome.

Hepatitis B virus (HBV) infection causes Hepatitis B, which is one of the most common causes of hepatocellular carcinoma (HCC). The single nucleotide polymorphisms (SNPs) of the host immune genes could impact HBV infection, viral clearance, and treatment effect. However, the contradictory roles of several studies suggest further analysis of various populations. The whole blood and biochemical indexes of 448 HBV patients and matched controls were collected from the Yunnan population to investigate the genetic roles of IFNL4 and the downstream genes (MxA and MxB). The genotypes, alleles, and haplotypes frequencies of the seven SNPs (rs11322783, rs117648444, rs2071430, rs17000900, rs9982944, rs408825, and rs2838029) from the HBV patients and controls were analyzed. However, no association was identified between the SNPs and HBV infection. Then, biochemical index levels were evaluated among the HBV patients with different genotypes of the seven SNPs. The results indicated that the liver function index levels (including alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), and albumin (ALB)) were influenced by the genotypes of the SNPs in HBV patients. Moreover, when the HBV patients were divided into HBsAg-positive and -negative groups, the association between the SNP genotypes and the biochemical indexes still existed. In addition, although the genetic polymorphisms in the IFNL4, MxA, and MxB genes were not significantly associated with HBV infection in the Yunnan population, these genes could indirectly influence disease progression by associating with the biochemical index levels of Yunnan HBV patients.

Host proteins sense viral products and induce defence mechanisms, particularly in immune cells. Using cell-free assays and quantitative mass spectrometry, we determined the interactome of capsid-host protein complexes of herpes simplex virus and identified the large dynamin-like GTPase myxovirus resistance protein B (MxB) as an interferon-inducible protein interacting with capsids. Electron microscopy analyses showed that cytosols containing MxB had the remarkable capability to disassemble the icosahedral capsids of herpes simplex viruses and varicella zoster virus into flat sheets of connected triangular faces. In contrast, capsids remained intact in cytosols with MxB mutants unable to hydrolyse GTP or to dimerize. Our data suggest that MxB senses herpesviral capsids, mediates their disassembly, and thereby restricts the efficiency of nuclear targeting of incoming capsids and/or the assembly of progeny capsids. The resulting premature release of viral genomes from capsids may enhance the activation of DNA sensors, and thereby amplify the innate immune responses.

The human myxovirus resistance B (MxB) protein is an interferon-induced restriction factor that fights a wide range of viruses. We previously demonstrated that MxB binds to hepatitis C virus (HCV)-encoded non-structural protein 5A (NS5A) and inhibits HCV infection by impairing the formation of cyclophilin A (CypA)-NS5A complex. However, the molecular details about how the presence of MxB diminishes the binding of NS5A to CypA remain uncovered. In this study, through molecular dynamic simulations and biochemical assays, we characterized that MxB binds to NS5A domain I through its N-terminal and GTPase domains. Specifically, amino acids (aa.) 189-191 and aa. 330-334 within MxB, together with NS5A residues aa. 71-73, are crucial for MxB-NS5A interaction. Furthermore, we predicted the CypA:NS5A and CypA:NS5A:MxB complexes and calculated the per-residue energy decomposition for identified key residues of the CypA-NS5A interface. A 28% decrease in CypA-NS5A binding affinity was observed in the presence of MxB, suggesting a weakened CypA-NS5A association upon binding of MxB to NS5A, which may contribute to the MxB-mediated inhibitory effect on the formation of CypA-NS5A complex. This work provides information for the antiviral mechanism of MxB and may facilitate the discovery of new strategies to combat CypA-dependent viruses.

Interferon exerts its antiviral activity by stimulating the expression of antiviral proteins. These interferon stimulate genes (ISGs) often target a group of viruses with unique molecular mechanisms. One such ISG is myxovirus resistance B (MxB) that has been reported to inhibit human immunodeficiency virus type 1 (HIV-1) by targeting viral capsid and impairing nuclear import of viral DNA. The antiviral specificity of MxB is determined by its N-terminal 25 amino acids sequence which has the nuclear localization activity, therefore functions as a nuclear localization signal (NLS). In this study, we report that the bipartite NLS, but not the classic NLS, the PY-NLS, nor the arginine-rich NLS, when used to replace the N-terminal sequence of MxB, drastically suppress HIV-1 gene expression and virus production, thus creates a new anti-HIV-1 mechanism. MxB preserves its anti-HIV-1 activity when its N-terminal sequence is replaced by the arginine-rich NLS. Interestingly, the arginine-rich NLS allows MxB to inhibit HIV-1 CA mutants that are otherwise resistant to wild type MxB, which suggests sequence specific targeting of viral capsid. Together, these data implicate that it is not the nuclear import function itself, but rather the sequence and the mechanism of action of the NLS which define the antiviral property of MxB.

Mx proteins are interferon (IFN) type I (α/β)- and type III (λ)-induced effector proteins with intrinsic antiviral activity. Mammalian Mx proteins show different subcellular localizations and distinct yet partially overlapping viral specificities. However, the precise mechanism(s) of antiviral action are still unresolved. Human MxA accumulates in the cytoplasm and inhibits a wide variety of RNA and DNA viruses, among them influenza A virus (IAV). In contrast, MxB, the second human Mx protein, localizes via its amino (N) terminus to the outer nuclear membrane at or near nuclear pores and inhibits the nuclear import of incoming human immunodeficiency viruses (HIV) and herpesviruses, but not that of IAV. Here, we evaluated whether the antiviral specificity of MxB is determined by its subcellular localization. For this purpose, we redirected MxB to the nucleus or cytoplasm by either attaching a nuclear localization signal to its N terminus or by exchanging the N terminus of MxB with that of MxA. Interestingly, ectopic expression of these MxB variants in the nucleus or in the cytoplasm rendered the host cells resistant to IAV, revealing that the capacity of MxB to block IAV replication critically depends on the site where the protein accumulates in the infected cell. Furthermore, coimmunoprecipitation (co-IP) assays demonstrated that MxB physically interacted with the nucleoprotein (NP) of IAV. Taken together, the data indicate that the subcellular localization of the MxB protein plays a pivotal role in determining its antiviral specificity.IMPORTANCE The interferon system plays a pivotal role in the defense against viral infections. The dynamin-related Mx proteins form a small family of interferon-induced effector proteins with distinct antiviral specificities and subcellular localizations. So far, it is not clear whether the different virus specificities of Mx proteins are the result of distinct mechanisms of action or are due rather to their different subcellular localization. We show here that the human MxB protein, normally localized to the outer membrane of the cell nucleus, acquires antiviral activity against IAV when redirected to the nucleus or cytoplasm, subcellular sites where other members of the Mx protein family efficiently interfere with IAV replication. Our findings thus strongly suggest that Mx proteins act primarily through a common mechanism and that their viral specificity is at least in part determined by their individual subcellular localization.

The interferon-inducible myxovirus resistance B (MxB) protein has been reported to inhibit HIV-1 and herpesviruses by blocking the nuclear import of viral DNA. Here, we report a new antiviral mechanism in which MxB restricts the nuclear import of HIV-1 regulatory protein Rev, and as a result, diminishes Rev-dependent expression of HIV-1 Gag protein. Specifically, MxB disrupts the interaction of Rev with the nuclear transport receptor, transportin 1 (TNPO1). Supporting this, the TNPO1-independent Rev variants become less restricted by MxB. In addition, HIV-1 can overcome this inhibition by MxB through increasing the expression of multiply spliced viral RNA and hence Rev protein. Therefore, MxB exerts its anti-HIV-1 function through interfering with the nuclear import of both viral DNA and viral Rev protein.