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Interferon induced IFIT family genes in host antiviral defense.

Zhou X, Michal JJ, Zhang L, Ding B, Lunney JK, Liu B, Jiang Z - Int. J. Biol. Sci. (2013)

Bottom Line: IFIT family genes are predominantly induced by type I and type III interferons and are regulated by the pattern recognition and the JAK-STAT signaling pathway.IFIT family proteins are involved in many processes in response to viral infection.We believe that our current review provides a comprehensive picture for the community to understand the structure and function of IFIT family genes in response to pathogens in human, as well as in animals.

View Article: PubMed Central - PubMed

Affiliation: Department of Animal Sciences, Washington State University, Pullman, WA 99164-6351, USA.

ABSTRACT
Secretion of interferons (IFNs) from virus-infected cells is a hallmark of host antiviral immunity and in fact, IFNs exert their antiviral activities through the induction of antiviral proteins. The IFN-induced protein with tetratricopeptide repeats (IFITs) family is among hundreds of IFN-stimulated genes. This family contains a cluster of duplicated loci. Most mammals have IFIT1, IFIT2, IFIT3 and IFIT5; however, bird, marsupial, frog and fish have only IFIT5. Regardless of species, IFIT5 is always adjacent to SLC16A12. IFIT family genes are predominantly induced by type I and type III interferons and are regulated by the pattern recognition and the JAK-STAT signaling pathway. IFIT family proteins are involved in many processes in response to viral infection. However, some viruses can escape the antiviral functions of the IFIT family by suppressing IFIT family genes expression or methylation of 5' cap of viral molecules. In addition, the variants of IFIT family genes could significantly influence the outcome of hepatitis C virus (HCV) therapy. We believe that our current review provides a comprehensive picture for the community to understand the structure and function of IFIT family genes in response to pathogens in human, as well as in animals.

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Antiviral and immune regulated function of IFIT family genes. IFIT1 and IFIT2 directly bind eIF3 and suppress transcription of virus genes. IFIT1, IFIT2 and IFIT3 form a complex in cytoplasm that recognizes and kills PPP-RNA. IFIT5 may also kill PPP-RNA directly. IFIT1 disrupts the interaction of MITA, MAVS and TBK1, which then negatively regulates the cellular antiviral response. IFIT2 interacts with MITA, and induces apoptosis via the mitochondrial pathway that is induced by the innate immune response. IFIT3 bridges TBK1 to MAVS in mitochondria, which synergizes the activation of IRF3 and NF-κB to activate the immune response.
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Figure 4: Antiviral and immune regulated function of IFIT family genes. IFIT1 and IFIT2 directly bind eIF3 and suppress transcription of virus genes. IFIT1, IFIT2 and IFIT3 form a complex in cytoplasm that recognizes and kills PPP-RNA. IFIT5 may also kill PPP-RNA directly. IFIT1 disrupts the interaction of MITA, MAVS and TBK1, which then negatively regulates the cellular antiviral response. IFIT2 interacts with MITA, and induces apoptosis via the mitochondrial pathway that is induced by the innate immune response. IFIT3 bridges TBK1 to MAVS in mitochondria, which synergizes the activation of IRF3 and NF-κB to activate the immune response.

Mentions: IFIT family proteins are involved in many processes in response to viral infection, mainly by reducing virus replication. The IFIT family proteins contain a TPR (tetratricopeptide repeat) domain, a 34 amino acid motif folding in to a helix-turn-helix structure, which mediates protein interactions 4. IFIT1 and IFIT2 are involved in a nonspecific antiviral program through their direct interactions with eIF3, which subsequently suppresses more than 60% of translation in cells and viruses during protein synthesis (Figure 4) 37-39. The IFIT family, especially IFIT1 and IFIT3, restrict DNA and RNA virus replication, such as hepatitis B virus (HBV), human papillomavirus (HPV), hepatitis C virus (HCV), West Nile virus (WNV) and others 13, 17, 28, 40-41. Knockdown of IFIT1 though RNA interference in human hepatocytes enhanced HCV replication during infection 40. Similar results were also observed in other IFIT family members during other viral infections 28. Although, IFIT family genes commonly restrict virus replication through alternation of protein synthesis, more mechanisms need to be explored. An intriguing, newly found antiviral mechanism of IFIT family genes is the ability of IFIT family proteins to directly bind viral RNA. Viral RNA that carries 5'PPP-RNA is recognized by IFIT1, followed by sequestering with the IFIT complex that contains IFIT1, IFIT2 and IFIT3. IFIT5, which shares the highest sequence homology with IFIT1, is also associated with PPP-RNA, but has little interaction with IFIT2 and IFIT3 (Figure 4) 28. These data provide evidence that the IFIT family members play an important role in killing invasive RNA. Working together with other ISGs, they are able to restrict virus replication. In addition, IFIT2 may limit replication of vesicular stomatitis virus (VSV) in brain. Virus titer was higher in ifit2 (-/-) mice compared to wild-type mice during VSV infection. However, ifit1 could not prevent VSV replication 42.


Interferon induced IFIT family genes in host antiviral defense.

Zhou X, Michal JJ, Zhang L, Ding B, Lunney JK, Liu B, Jiang Z - Int. J. Biol. Sci. (2013)

Antiviral and immune regulated function of IFIT family genes. IFIT1 and IFIT2 directly bind eIF3 and suppress transcription of virus genes. IFIT1, IFIT2 and IFIT3 form a complex in cytoplasm that recognizes and kills PPP-RNA. IFIT5 may also kill PPP-RNA directly. IFIT1 disrupts the interaction of MITA, MAVS and TBK1, which then negatively regulates the cellular antiviral response. IFIT2 interacts with MITA, and induces apoptosis via the mitochondrial pathway that is induced by the innate immune response. IFIT3 bridges TBK1 to MAVS in mitochondria, which synergizes the activation of IRF3 and NF-κB to activate the immune response.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3584916&req=5

Figure 4: Antiviral and immune regulated function of IFIT family genes. IFIT1 and IFIT2 directly bind eIF3 and suppress transcription of virus genes. IFIT1, IFIT2 and IFIT3 form a complex in cytoplasm that recognizes and kills PPP-RNA. IFIT5 may also kill PPP-RNA directly. IFIT1 disrupts the interaction of MITA, MAVS and TBK1, which then negatively regulates the cellular antiviral response. IFIT2 interacts with MITA, and induces apoptosis via the mitochondrial pathway that is induced by the innate immune response. IFIT3 bridges TBK1 to MAVS in mitochondria, which synergizes the activation of IRF3 and NF-κB to activate the immune response.
Mentions: IFIT family proteins are involved in many processes in response to viral infection, mainly by reducing virus replication. The IFIT family proteins contain a TPR (tetratricopeptide repeat) domain, a 34 amino acid motif folding in to a helix-turn-helix structure, which mediates protein interactions 4. IFIT1 and IFIT2 are involved in a nonspecific antiviral program through their direct interactions with eIF3, which subsequently suppresses more than 60% of translation in cells and viruses during protein synthesis (Figure 4) 37-39. The IFIT family, especially IFIT1 and IFIT3, restrict DNA and RNA virus replication, such as hepatitis B virus (HBV), human papillomavirus (HPV), hepatitis C virus (HCV), West Nile virus (WNV) and others 13, 17, 28, 40-41. Knockdown of IFIT1 though RNA interference in human hepatocytes enhanced HCV replication during infection 40. Similar results were also observed in other IFIT family members during other viral infections 28. Although, IFIT family genes commonly restrict virus replication through alternation of protein synthesis, more mechanisms need to be explored. An intriguing, newly found antiviral mechanism of IFIT family genes is the ability of IFIT family proteins to directly bind viral RNA. Viral RNA that carries 5'PPP-RNA is recognized by IFIT1, followed by sequestering with the IFIT complex that contains IFIT1, IFIT2 and IFIT3. IFIT5, which shares the highest sequence homology with IFIT1, is also associated with PPP-RNA, but has little interaction with IFIT2 and IFIT3 (Figure 4) 28. These data provide evidence that the IFIT family members play an important role in killing invasive RNA. Working together with other ISGs, they are able to restrict virus replication. In addition, IFIT2 may limit replication of vesicular stomatitis virus (VSV) in brain. Virus titer was higher in ifit2 (-/-) mice compared to wild-type mice during VSV infection. However, ifit1 could not prevent VSV replication 42.

Bottom Line: IFIT family genes are predominantly induced by type I and type III interferons and are regulated by the pattern recognition and the JAK-STAT signaling pathway.IFIT family proteins are involved in many processes in response to viral infection.We believe that our current review provides a comprehensive picture for the community to understand the structure and function of IFIT family genes in response to pathogens in human, as well as in animals.

View Article: PubMed Central - PubMed

Affiliation: Department of Animal Sciences, Washington State University, Pullman, WA 99164-6351, USA.

ABSTRACT
Secretion of interferons (IFNs) from virus-infected cells is a hallmark of host antiviral immunity and in fact, IFNs exert their antiviral activities through the induction of antiviral proteins. The IFN-induced protein with tetratricopeptide repeats (IFITs) family is among hundreds of IFN-stimulated genes. This family contains a cluster of duplicated loci. Most mammals have IFIT1, IFIT2, IFIT3 and IFIT5; however, bird, marsupial, frog and fish have only IFIT5. Regardless of species, IFIT5 is always adjacent to SLC16A12. IFIT family genes are predominantly induced by type I and type III interferons and are regulated by the pattern recognition and the JAK-STAT signaling pathway. IFIT family proteins are involved in many processes in response to viral infection. However, some viruses can escape the antiviral functions of the IFIT family by suppressing IFIT family genes expression or methylation of 5' cap of viral molecules. In addition, the variants of IFIT family genes could significantly influence the outcome of hepatitis C virus (HCV) therapy. We believe that our current review provides a comprehensive picture for the community to understand the structure and function of IFIT family genes in response to pathogens in human, as well as in animals.

Show MeSH
Related in: MedlinePlus