Mx GTPases: dynamin-like antiviral machines of innate immunity

Haller, Otto; Staeheli, Peter; Schwemmle, Martin; Kochs, Georg

doi:10.1016/j.tim.2014.12.003

Cited by 382 publications

(516 citation statements)

References 109 publications

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confidence: 99%

“…The innate immune factor shows antiviral activity against a broad range of RNA and DNA viruses including orthomyxo-, bunya-, rhabdo-and paramyxoviruses as well as African swine fever virus and hepatitis B virus (1). Its expression is not directly induced by viruses but by type I (α/β) and III (λ) interferons (1). MxA, a dynamin-like GTPase, can be structurally subdivided into three domains: an N-terminal GTPase domain (G domain), that binds and hydrolyses GTP; an antiparallel four-helical bundle called the stalk; and a connecting three-helical bundle denominated as the bundle signaling element (BSE) (Fig.…”

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confidence: 99%

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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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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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“…M yxovirus resistance proteins represent a family of interferon-inducible factors with a wide range of antiviral activities (1)(2)(3). The myxovirus B (MxB) gene was originally cloned from a human glioblastoma cell line treated with alpha interferon (IFN-␣) (4,5).…”

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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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“…MX GTPAses play key roles in viral immunity, and myxovirus resistance A genes are up-regulated by ifnγ signaling [38], as are stat1a and stat1b. Vertebrate Mx were compared, and similarities grouped them into fish mx, avian mx, human mx2-like, and human mx1-like [39].…”

Section: Primary Responsementioning

confidence: 99%

Transcriptome Changes Associated with Protective Immunity in T and B Cell-Deficient <i>Rag1<sup>-/-</sup> </i> Mutant Zebrafish

Krishnavajhala¹,

Muire²,

Hanson³

et al. 2017

IJI

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Abstract:To elucidate the basis of protective immunity in T and B cell deficient rag1 -/-mutant zebrafish, we conducted microarray analysis of 15,617 genes from rag1 -/-mutant zebrafish 48 hours after a primary response and 48 hours after a secondary response. Following primary exposure, the highest fold expression differences (3.8 to 4.95) were genes for serum amyloid A, chemokine CCL-C5a (CCL-19a), signal transducer and activator of transcription (STAT) 1b, interferon regulatory factor 11, and myxovirus resistance A. Strong induction of these genes demonstrated that primary immune responses and innate immune cells were not impaired in T and B cell deficient mutant zebrafish. Following bacterial re-exposure, the highest fold expression differences (2 to 3 fold) were in chemokine CCL-C5a (CCL-19a), myomegalin, bone morphogenetic protein 4, and relaxin 3a. These genes are involved in the immune response and cell proliferation. Genes for cell receptor activation and signal transduction, cell proliferation and cytotoxic functions were also up-regulated. These findings suggest receptor activation and expansion of a cell population. Increased ifnγ expression at 48 hpi was associated with both primary and secondary immune responses.

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Mx GTPases: dynamin-like antiviral machines of innate immunity

Cited by 382 publications

References 109 publications

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

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

Transcriptome Changes Associated with Protective Immunity in T and B Cell-Deficient <i>Rag1<sup>-/-</sup> </i> Mutant Zebrafish

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Mx GTPases: dynamin-like antiviral machines of innate immunity

Cited by 382 publications

References 109 publications

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

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

Transcriptome Changes Associated with Protective Immunity in T and B Cell-Deficient &lt;i&gt;Rag1&lt;sup&gt;-/-&lt;/sup&gt; &lt;/i&gt; Mutant Zebrafish

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Transcriptome Changes Associated with Protective Immunity in T and B Cell-Deficient <i>Rag1<sup>-/-</sup> </i> Mutant Zebrafish