A Triple-Arginine Motif in the Amino-Terminal Domain and Oligomerization Are Required for HIV-1 Inhibition by Human MX2

Goujon, Caroline; Greenbury, Rebecca A.; Papaioannou, Stelios; Doyle, Tomas; Malim, Michael H.

doi:10.1128/jvi.00169-15

Cited by 61 publications

(108 citation statements)

References 28 publications

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“…Addition of the human MX2 NTD rendered otherwise inactive MX1 or canine Mx2 active against HIV-1 [92, 97]. Furthermore, artificial chimeric proteins harboring the MX2 NTD appended to otherwise unrelated restriction factors, such as Fv1 or SAMHD1 (SAM domain and HD domain-containing protein 1), potently restricted HIV-1 [98, 99]. The MX2 NTD possesses two critical functions for antiviral activity: subcellular localization and capsid binding.…”

Section: Mx2mentioning

confidence: 99%

“…Addition of the heterologous NLS from the simian virus 40 large T antigen conferred anti-HIV activity to MX2 lacking its own NLS [88]. The NTD is critical for MX2 binding to CA [94], with a triple arginine motif playing a particularly important role in binding and restriction, but not subcellular localization [98, 99]. Oligomerization is another MX2 property critical for its antiviral activity, and MX2 forms an extended antiparallel dimer [94, 100].…”

Section: Mx2mentioning

confidence: 99%

“…Oligomerization is another MX2 property critical for its antiviral activity, and MX2 forms an extended antiparallel dimer [94, 100]. Dimerization, but not higher-order oligomerization, which is mediated by the MX2 CTD, is essential for anti-HIV-1 activity [88, 89, 94, 98, 100–102]. Oligomerization is required for MX2 binding to capsid [94, 101].…”

Section: Mx2mentioning

confidence: 99%

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Capsid-Dependent Host Factors in HIV-1 Infection

Yamashita

Engelman

2017

Trends in Microbiology

113

112

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After invasion of a susceptible target cell, HIV-1 completes the early phase of its life cycle upon integration of reverse-transcribed viral DNA into host chromatin. The viral capsid, a conical shell encasing the viral ribonucleoprotein complex, along with its constitutive capsid protein plays essential roles at virtually every step in the early phase of the viral life cycle. Recent work has begun to reveal how the viral capsid interacts with specific cellular proteins to promote these processes. At the same time, cellular restriction factors target the viral capsid to thwart infection. Comprehensive understanding of capsid-host interactions that promote or impede HIV-1 infection may provide unique insight to exploit for novel therapeutic interventions.

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Section: Mx2mentioning

confidence: 99%

Section: Mx2mentioning

confidence: 99%

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Capsid-Dependent Host Factors in HIV-1 Infection

Yamashita

Engelman

2017

Trends in Microbiology

113

112

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“…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).…”

mentioning

confidence: 99%

“…Afterwards, the lysate was centrifuged at maximum speed in a refrigerated Eppendorf microcentrifuge (ϳ14,000 ϫ g) for 5 min. Cell lysates were incubated with in vitro-assembled HIV-1 CA-NC complexes for 1 h at room temperature (28,29). A fraction of this mixture was stored (input).…”

mentioning

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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Overexpression of human MX2 gene suppresses cell proliferation, migration, and invasion via ERK/P38/NF‐κB pathway in glioblastoma cells

Wang

Guan

Yang

et al. 2019

J of Cellular Biochemistry

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In human, there are two myxovirus resistance genes—MX1 and MX2, which respectively encode MXA and MXB protein. For MXB, it was traditionally deemed to work in the progression of cell cycle and adjustment of nuclear import. Thus, we speculated that it might play important roles in tumor progression. The purpose of this study was to preliminarily explore the underlying functions and mechanism of the MX2 gene on glioblastoma multiforme. Quantitative reverse transcription polymerase chain reaction, 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazoliumbromide (MTT), and transwell experiments were to detect the relative MX2 mRNA level and its biological functions on glioma cells, respectively. The data displayed that MX2 was obviously downregulated both in glioblastoma (GBM) and GBM cell lines, meanwhile, its overexpression could markedly reduce cell proliferation, migration, and invasion of glioma cells, implying that it was related with glioblastoma progression. In addition, the overall survival of patient with glioblastoma had a negative correlation with the MX2 expression. Then, Western blot indicated the potential mechanism of MX2 in glioblastoma. We found that MX2 overexpression could decrease the relative levels of phosphorylated‐ERK1/2 (p‐ERK1/2), p‐p38, and nuclear factor‐κB (NF‐κB), while have no effects on extracellular signal‐regulated kinase (ERK), p38, and lamin B1. Moreover, the influences of MX2 overexpression on cell proliferation, migration, and invasion could be weakened by the three inhibitors (PD98059, SB203580, and (pyridin‐2‐ylmethyl) dithiocarbamate [PDTC]). These results implied that MX2 might suppress the proliferation and metastasis of glioma cells by manipulating the ERK/P38/NF‐κB signaling pathway. In conclusion, MX2 is potential to be a new marker used for glioblastoma prognosis or a new target for glioblastoma treatments.

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A Triple-Arginine Motif in the Amino-Terminal Domain and Oligomerization Are Required for HIV-1 Inhibition by Human MX2

Cited by 61 publications

References 28 publications

Capsid-Dependent Host Factors in HIV-1 Infection

Capsid-Dependent Host Factors in HIV-1 Infection

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

Overexpression of human MX2 gene suppresses cell proliferation, migration, and invasion via ERK/P38/NF‐κB pathway in glioblastoma cells

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