Identification of an endocytic signal essential for the antiviral action of IFITM3

Jia, Rui; Xu, Feifei; Qian, Jin; Yao, Yunfang; Miao, Chunhui; Zheng, Yi-Min; Liu, Shan-Lu; Guo, Fei; Geng, Yi; Qiao, Wentao; Liang, Chen

doi:10.1111/cmi.12262

Cited by 119 publications

(185 citation statements)

References 41 publications

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“…We found IFITM3 to be more potent than IFITM1 in its inhibition of Zika virus replication. Consistent with this, the loss of a specific endocytosis motif required for the proper localization of IFITM3 is necessary for maximal viral restriction (Jia et al, 2014;John et al, 2013). We also revealed that Zika virus causes a cytopathic effect in HeLa cells and that IFITM3 modulates this phenotype.…”

Section: Introductionsupporting

confidence: 81%

“…In keeping with these observations, overexpressed IFITM1 did inhibit Zika virus replication (MR766 and FSS13025 strains), but to a lesser extent than IFITM3, with the caveat that we cannot compare the levels of these two untagged proteins directly (Figures 2A-2C). An IFITM3 mutant, Y20A, which harbors a mutation in a clathrin-mediated endocytosis motif required for proper protein localization in the endosomal pathway, also demonstrated a moderately reduced ability to block viral replication (Jia et al, 2014;John et al, 2013).…”

Section: Ifitm1 Inhibits Zika Virus Replication and The Proper Localmentioning

confidence: 99%

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The IFITMs Inhibit Zika Virus Replication

et al. 2016

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Zika virus has emerged as a severe health threat with a rapidly expanding range. The IFITM family of restriction factors inhibits the replication of a broad range of viruses, including the closely related flaviruses West Nile virus and dengue virus. Here, we show that IFITM1 and IFITM3 inhibit Zika virus infection early in the viral life cycle. Moreover, IFITM3 can prevent Zika-virus-induced cell death. These results suggest that strategies to boost the actions and/or levels of the IFITMs might be useful for inhibiting a broad range of emerging viruses.

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Section: Introductionsupporting

confidence: 81%

Section: Ifitm1 Inhibits Zika Virus Replication and The Proper Localmentioning

confidence: 99%

The IFITMs Inhibit Zika Virus Replication

et al. 2016

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“…5, 7 Obstructing the endocytosis of IFITM3 protein reduces its ability to inhibit influenza virus infection. 30 The rs12252 minor C allele creates a predicted splice site that would generate a putative, truncated IFITM3 transcript lacking the first 21 N-terminal amino acids (Δ1-21 variant), 3 including the Y20 amino acid, located in a motif that is recognized and bound by the AP-2 complex leading to trafficking of IFITM3 protein to endosomes and lysosomes. 30 The Δ1-21 variant protein was shown to accumulate at the plasma membrane rather than at endosomal membranes and to have reduced activity to restrict influenza virus infection in vitro .…”

Section: Discussionmentioning

confidence: 99%

Pilot screening study of targeted genetic polymorphisms for association with seasonal influenza hospital admission

Carter

Hebbring

Liu

et al. 2017

Journal of Medical Virology

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Host response to influenza is highly variable, suggesting a potential role of host genetic variation. To investigate the host genetics of severe influenza in a targeted fashion, 32 single nucleotide polymorphisms (SNPs) within viral immune response genes were evaluated for association with seasonal influenza hospitalization in an adult study population with European ancestry. SNP allele and genotype frequencies were compared between hospitalized influenza patients (cases) and population controls in a case-control study that included a discovery group (26 cases and 993 controls) and two independent, validation groups (1 with 84 cases and 4076 controls; the other with 128 cases and 9187 controls). Cases and controls had similar allele frequencies for variant rs12252 in interferon-inducible transmembrane protein 3 (IFITM3) (P > 0.05), and the study did not replicate the previously reported association of rs12252 with hospitalized influenza. In the discovery group, the preliminary finding of an association with a nonsense polymorphism (rs8072510) within the schlafen family member 13 (SFLN13) gene (P = 0.0099) was not confirmed in either validation group. Neither rs12252 nor rs8072510 showed an association according to the presence of clinical risk factors for influenza complications (P > 0.05), suggesting that these factors did not modify associations between the SNPs and hospitalized influenza. No other SNPs showed a statistically significant association with hospitalized influenza. Further research is needed to identify genetic factors involved in host response to seasonal influenza infection and to assess whether rs12252, a low-frequency variant in Europeans, contributes to influenza severity in populations with European ancestry.

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“…There is an endocytic signal in IFITM proteins responsible for antiviral activity (51). Interestingly, prolonged passage of HIV in IFITM-expressing T lymphocytes leads to emergence of Env mutants that overcome IFITM restriction.…”

Section: Figmentioning

confidence: 99%

JAK-STAT Signaling Pathways and Inhibitors Affect Reversion of Envelope-Mutated HIV-1

Quan

Han

et al. 2017

J Virol

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HIV can spread by both cell-free and cell-to-cell transmission. Here, we show that many of the amino acid changes in Env that are close to the CD4 binding pocket can affect HIV replication. We generated a number of mutant viruses that were unable to infect T cells as cell-free viruses but were nevertheless able to infect certain T cell lines as cell-associated viruses, which was followed by reversion to the wild type. However, the activation of JAK-STAT signaling pathways caused the inhibition of such cell-to-cell infection as well as the reversion of multiple HIV Env mutants that displayed differences in their abilities to bind to the CD4 receptor. Specifically, two T cell activators, interleukin-2 (IL-2) and phorbol 12-myristate 13-acetate (PMA), both capable of activation of JAK-STAT pathways, were able to inhibit cell-tocell viral transmission. In contrast, but consistent with the above result, a number of JAK-STAT and mTOR inhibitors actually promoted HIV-1 transmission and reversion. Hence, JAK-STAT signaling pathways may differentially affect the replication of a variety of HIV Env mutants in ways that differ from the role that these pathways play in the replication of wild-type viruses.IMPORTANCE Specific alterations in HIV Env close to the CD4 binding site can differentially change the ability of HIV to mediate infection for cell-free and cell-associated viruses. However, such differences are dependent to some extent on the types of target cells used. JAK-STAT signaling pathways are able to play major roles in these processes. This work sheds new light on factors that can govern HIV infection of target cells.KEYWORDS HIV-1, Env mutant, cell-associated viruses, cell dependence, reversion H IV-1 infection of cells can be efficiently established by free virus or directly via cell-cell contact, both involving the binding of the HIV gp120 protein to the cellular CD4 receptor and either the CCR5 or CXCR4 coreceptor (1-3). It has been reported that cell-to-cell transmission is more physiologically relevant and efficient although cell-free HIV may be used to initiate new infections in tissue culture (4-7).HIV-1 entry into target cells is believed to be a multistep and complex process initiated by the envelope protein gp120 binding to cell surface CD4, triggering conformational changes of gp120, followed by a second-step interaction between gp120 and either CXCR4 or CCR5, resulting in fusion between the viral envelope and the cellular plasma membrane (8). In addition to viral gp120 and other viral proteins, several host cell components, including intrinsic immune factors (9) and histocompatibility antigens, can influence HIV infectivity (10, 11). However, some viral factors can also counteract innate host defense mechanisms (12). It has also been reported that HIV can under some circumstances enter target cells via a CD4/coreceptor-independent mechanism (13-18), potentially broadening the spectrum of cells that HIV is able to infect.

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Identification of an endocytic signal essential for the antiviral action of IFITM3

Cited by 119 publications

References 41 publications

The IFITMs Inhibit Zika Virus Replication

The IFITMs Inhibit Zika Virus Replication

Pilot screening study of targeted genetic polymorphisms for association with seasonal influenza hospital admission

JAK-STAT Signaling Pathways and Inhibitors Affect Reversion of Envelope-Mutated HIV-1

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