IFIT3 and IFIT2/3 promote IFIT1-mediated translation inhibition by enhancing binding to non-self RNA.
Authors
Fleith, Renata C
Mears, Harriet
Leong, Xin Yun
Emmott, Edward
Mansur, Daniel S
Publication Date
2018-06-01Journal Title
Nucleic Acids Res
ISSN
0305-1048
Publisher
Oxford University Press (OUP)
Volume
46
Issue
10
Pages
5269-5285
Language
eng
Type
Article
This Version
VoR
Physical Medium
Print
Metadata
Show full item recordCitation
Fleith, R. C., Mears, H., Leong, X. Y., Sanford, T., Emmott, E., Graham, S., Mansur, D. S., & et al. (2018). IFIT3 and IFIT2/3 promote IFIT1-mediated translation inhibition by enhancing binding to non-self RNA.. Nucleic Acids Res, 46 (10), 5269-5285. https://doi.org/10.1093/nar/gky191
Abstract
Interferon-induced proteins with tetratricopeptide repeats (IFITs) are highly expressed during the cell-intrinsic immune response to viral infection. IFIT1 inhibits translation by binding directly to the 5' end of foreign RNAs, particularly those with non-self cap structures, precluding the recruitment of the cap-binding eukaryotic translation initiation factor 4F and ribosome recruitment. The presence of IFIT1 imposes a requirement on viruses that replicate in the cytoplasm to maintain mechanisms to avoid its restrictive effects. Interaction of different IFIT family members is well described, but little is known of the molecular basis of IFIT association or its impact on function. Here, we reconstituted different complexes of IFIT1, IFIT2 and IFIT3 in vitro, which enabled us to reveal critical aspects of IFIT complex assembly. IFIT1 and IFIT3 interact via a YxxxL motif present in the C-terminus of each protein. IFIT2 and IFIT3 homodimers dissociate to form a more stable heterodimer that also associates with IFIT1. We show for the first time that IFIT3 stabilizes IFIT1 protein expression, promotes IFIT1 binding to a cap0 Zika virus reporter mRNA and enhances IFIT1 translation inhibition. This work reveals molecular aspects of IFIT interaction and provides an important missing link between IFIT assembly and function.
Keywords
Humans, Multiprotein Complexes, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Proteins, Carrier Proteins, RNA-Binding Proteins, RNA, Messenger, RNA Caps, Chromatography, Gel, Protein Biosynthesis, Genes, Reporter, Apoptosis Regulatory Proteins, Host-Pathogen Interactions, HEK293 Cells, Zika Virus
Sponsorship
This work was supported by a joint Royal Society/Wellcome Trust Sir Henry Dale Fellowship (202471/Z/16/Z) and a Royal Society Research Grant (RG140708) to TRS. HVM is supported by a University of Cambridge, Department of Pathology PhD studentship. XYL is supported by a King’s Scholarship from the Malaysian government. TJS is supported by a Wellcome Trust PhD studentship (105389/Z/14/Z). RCF and DSM are supported by CAPES Computational Biology (23038.010048/2013-27). DSM is also supported by the Academy of Medical Sciences/UK (NAF004/1005). SCG is a Sir Henry Dale Fellow (098406/Z/12/Z) co-funded by the Wellcome Trust and Royal Society.
Funder references
Royal Society (RG2015 R1)
Wellcome Trust (202471/Z/16/Z)
Wellcome Trust (098406/Z/12/Z)
Wellcome Trust (105389/Z/14/Z)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1093/nar/gky191
This record's URL: https://www.repository.cam.ac.uk/handle/1810/275950
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