Grouper interferon-induced transmembrane protein 3 (IFITM3) inhibits the infectivity of iridovirus and nodavirus by restricting viral entry

Ya, Zhang; Huang, Youhua; Wang, Liqun; Huang, Liwei; Zheng, Jiaying; Huang, Xiaohong; Qin, Qiwei

doi:10.1016/j.fsi.2020.06.001

Cited by 10 publications

(4 citation statements)

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“…In another experimental group, GS cells were grown in glass bottom cell culture dishes (35 mm) and transfected with pEGFP-EcIFITM1 or pEGFP-C1 for 24 h. The cells were pre-chilled at 4°C for 5 min and infected with purified SGIV particles labeled with Alex-Fluor 647 labeled SGIV (MOI = 10) as previously described ( 38 , 39 , 44 , 45 ). The cells were observed under CLSM and photographed.…”

Section: Methodsmentioning

confidence: 99%

“…To clarify the host immune defense response against these two viruses ( 32 , 33 ), numerous immune genes involved in virus infection have been characterized, such as IFN regulatory factor (IRF) 3 ( 34 ), IRF7 ( 35 ), mitochondrial antiviral signaling protein (MAVS) ( 36 ), stimulator of interferon genes (STING) ( 37 ), and cholesterol 25-hydroxylase (CH25H) ( 38 ). Recently, we found that grouper IFITM3 restricted viral entry to suppress iridovirus or nodavirus infectivity ( 39 ). Whether other IFITM members exerted crucial roles during grouper virus infection is worthy of investigation.…”

Section: Introductionmentioning

confidence: 99%

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Grouper Interferon-Induced Transmembrane Protein 1 Inhibits Iridovirus and Nodavirus Replication by Regulating Virus Entry and Host Lipid Metabolism

Wang

Zheng

et al. 2021

Front. Immunol.

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Interferon-induced transmembrane proteins (IFITMs) are novel viral restriction factors which inhibit numerous virus infections by impeding viral entry into target cells. To investigate the roles of IFITMs during fish virus infection, we cloned and characterized an IFITM1 homolog from orange spotted grouper (Epinephelus coioides) (EcIFITM1) in this study. EcIFITM1 encodes a 131-amino-acid polypeptide, which shares 64 and 43% identity with Seriola dumerili and Homo sapiens, respectively. The multiple sequence alignment showed that EcIFITM1 contained five domains, including NTD (aa 1–45), IMD (aa 46–67), CIL (aa 68–93), TMD (aa 94–119), and CTD (aa 120–131). In vitro, the level of EcIFITM1 mRNA expression was significantly up-regulated in response to Singapore grouper iridovirus (SGIV), or red-spotted grouper nervous necrosis virus (RGNNV) infection. EcIFITM1 encoded a cytoplasmic protein, which was partly colocalized with early endosomes, late endosomes, and lysosomes. The ectopic expression of EcIFITM1 significantly inhibited the replication of SGIV or RGNNV, which was demonstrated by the reduced virus production, as well as the levels of viral gene transcription and protein expression. In contrast, knockdown of EcIFITM1 using small interfering RNAs (siRNAs) promoted the replication of both viruses. Notably, EcIFITM1 exerted its antiviral activity in the step of viral entry into the host cells. Furthermore, the results of non-targeted lipometabolomics showed that EcIFITM1 overexpression induced lipid metabolism remodeling in vitro. All of the detected ceramides were significantly increased following EcIFITM1 overexpression, suggesting that EcIFITM1 may suppress SGIV entry by regulating the level of ceramide in the lysosomal system. In addition, EcIFITM1 overexpression positively regulated both interferon-related molecules and ceramide synthesis-related genes. Taken together, our results demonstrated that EcIFITM1 exerted a bi-functional role, including immune regulation and lipid metabolism in response to fish virus infections.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Grouper Interferon-Induced Transmembrane Protein 1 Inhibits Iridovirus and Nodavirus Replication by Regulating Virus Entry and Host Lipid Metabolism

Wang

Zheng

et al. 2021

Front. Immunol.

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“…In recent years, small interfering RNA ( 15 ) and overexpression-based screens ( 25 ) have confirmed that IFITM1, IFITM2, and IFITM3 possess broad-spectrum antiviral effects. It has been reported that IFITM proteins, when expressed in target cells, significantly inhibit more than ten families of viruses including Alphaviridae (Semliki Forest virus, Sindbis virus) ( 26 ), Arteriviridae (Porcine reproductive and respiratory syndrome virus), Asfarviridae (African swine fever virus) ( 27 , 28 ), Bunyaviridae (Rift valley fever virus, La Crosse virus, Andes virus, Hantaan virus) ( 29 – 32 ), Caliciviridae (Mouse norovirus) ( 33 ), Coronaviridae (SARS coronavirus) ( 22 , 30 , 34 , 35 ), Filoviridae (Marburg virus, Ebola virus) ( 22 , 36 , 37 ), Flaviviridae (Dengue virus, West Nile virus, Yellow fever virus, Zika virus, Omsk hemorrhagic fever virus, Hepatitis C virus, Classical swine Fever Virus, Japanese encephalitis virus and tick-borne encephalitis virus) ( 23 , 30 , 31 , 38 – 44 ), Iridoviridae (Singapore grouper iridovirus and frog iridovirus) ( 45 – 48 ), Nodaviridae(red spotted grouper nervous necrosis virus) ( 45 , 46 ), Orthomyxoviridae (Influenza A virus) ( 49 , 50 ), Paramyxoviridae (Respiratory Syncytial Virus) ( 51 – 54 ), Poxviridae (Vaccina virus) ( 55 ) Reoviridae (Reovirus) ( 56 ), Retroviridae (HIV-1 and Jaagsiekte sheep retrovirus) ( 24 , 30 , 57 , 58 ), Rhabdviridae (Vesicular stomatitis virus) ( 57 , 59 , 60 ), Phenuiviridae (Severe fever with thrombocytopenia syndrome virus) ( 33 ).…”

Section: Antiviral Activities Of Interferon-induced Transmembrane Pro...mentioning

confidence: 99%

Positive Regulation of the Antiviral Activity of Interferon-Induced Transmembrane Protein 3 by S-Palmitoylation

Wen

Song

et al. 2022

Front. Immunol.

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The interferon-induced transmembrane protein 3 (IFITM3), a small molecule transmembrane protein induced by interferon, is generally conserved in vertebrates, which can inhibit infection by a diverse range of pathogenic viruses such as influenza virus. However, the precise antiviral mechanisms of IFITM3 remain unclear. At least four post-translational modifications (PTMs) were found to modulate the antiviral effect of IFITM3. These include positive regulation provided by S-palmitoylation of cysteine and negative regulation provided by lysine ubiquitination, lysine methylation, and tyrosine phosphorylation. IFITM3 S-palmitoylation is an enzymatic addition of a 16-carbon fatty acid on the three cysteine residues within or adjacent to its two hydrophobic domains at positions 71, 72, and 105, that is essential for its proper targeting, stability, and function. As S-palmitoylation is the only PTM known to enhance the antiviral activity of IFITM3, enzymes that add this modification may play important roles in IFN-induced immune responses. This study mainly reviews the research progresses on the antiviral mechanism of IFITM3, the regulation mechanism of S-palmitoylation modification on its subcellular localization, stability, and function, and the enzymes that mediate the S-palmitoylation modification of IFITM3, which may help elucidate the mechanism by which this IFN effector restrict virus replication and thus aid in the design of therapeutics targeted at pathogenic viruses.

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“…To date, animal IFITM antiviral activities have been mostly evaluated in homologous host-species-virus settings; i.e. in cells of the same species and against viruses specific for that species (29,30,(38)(39)(40)(41), making a direct comparison of their antiviral potency difficult. Here, we aimed at comparing the antiviral behavior of the different IFITMs in a single cellular setting and to this end, both target cell protection and negative imprinting of virion's infectivity abilities of the different IFITMs were assessed against HIV-1.…”

Section: Articlementioning

confidence: 99%

Functional Heterogeneity of Mammalian IFITM Proteins against HIV-1

Marziali

Delpeuch

Kumar

et al. 2021

J Virol

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IFITMs are a family of interferon-inducible proteins that inhibit a broad range of viruses by interfering with viral to cellular membrane fusion. The antiviral activity of IFITMs is highly regulated by several post-translational modifications and by a number of protein domains that modulate steady-state protein levels, trafficking and antiviral effectiveness. Taking advantage of the natural diversity existing among IFITMs of different animal species, we have compared twenty-one IFITMs for their ability to inhibit HIV-1 at two steps: during virus entry into cells (target cell protection) and during the production of novel virion particles (negative imprinting of virion particles’ infectivity). We found a high functional heterogeneity among IFITM homologs with respect to both antiviral modalities, with IFITM members that exhibit enhanced viral inhibition, while others have no ability to block HIV-1. These differences could not be ascribed to known regulatory domains and could only be partially explained through differential protein stability, implying the existence of additional mechanisms. Through the use of chimeras between active and inactive IFITMs, we demonstrate that the cross-talk between distinct domains of IFITMs is an important contributor of their antiviral potency. Finally, we identified murine IFITMs as natural variants competent for target cell protection, but not for negative imprinting of virion particles’ infectivity, suggesting that the two properties may, at least in principle, be uncoupled. Overall, our results shed new light on the complex relationship between IFITMs and viral infection and point to the cross-talk between IFITM domains as a novel layer of regulation of their activity. IMPORTANCE IFITMs are broad viral inhibitors capable of interfering with both early and late phases of the replicative cycle of many different viruses. By comparing twenty-one IFITM proteins issued from different animal species for their ability to inhibit HIV-1, we have identified several that exhibit either enhanced or impaired antiviral behavior. This functional diversity is not driven by differences in known domains and can only be partly explained through differential protein stability. Chimeras between active and inactive IFITMs point to the cross-talk between individual IFITM domains as important for optimal antiviral activity. Finally, we show that murine IFITMs are not capable of decreasing the infectivity of newly-produced HIV-1 virion particles, although they retain target cell protection abilities, suggesting that these properties may be in principle disconnected. Overall, our results shed new light on the complex layers of regulation of IFITM proteins and enrich our current understanding on these broad antiviral factors.

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Grouper interferon-induced transmembrane protein 3 (IFITM3) inhibits the infectivity of iridovirus and nodavirus by restricting viral entry

Cited by 10 publications

References 53 publications

Grouper Interferon-Induced Transmembrane Protein 1 Inhibits Iridovirus and Nodavirus Replication by Regulating Virus Entry and Host Lipid Metabolism

Grouper Interferon-Induced Transmembrane Protein 1 Inhibits Iridovirus and Nodavirus Replication by Regulating Virus Entry and Host Lipid Metabolism

Positive Regulation of the Antiviral Activity of Interferon-Induced Transmembrane Protein 3 by S-Palmitoylation

Functional Heterogeneity of Mammalian IFITM Proteins against HIV-1

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