Human Genome-Wide RNAi Screen Identifies an Essential Role for Inositol Pyrophosphates in Type-I Interferon Response

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Human Genome-Wide RNAi Screen Identifies an Essential Role for Inositol Pyrophosphates in Type-I Interferon Response

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Title: Human Genome-Wide RNAi Screen Identifies an Essential Role for Inositol Pyrophosphates in Type-I Interferon Response
Author: Pulloor, Niyas Kudukkil; Nair, Sajith; Kostic, Aleksandar D.; Bist, Pradeep; Weaver, Jeremy D.; Riley, Andrew M.; Tyagi, Richa; Uchil, Pradeep D.; York, John D.; Snyder, Solomon H.; García-Sastre, Adolfo; Potter, Barry V. L.; Lin, Rongtuan; Shears, Stephen B.; Xavier, Ramnik J.; Krishnan, Manoj N.

Note: Order does not necessarily reflect citation order of authors.

Citation: Pulloor, N. K., S. Nair, A. D. Kostic, P. Bist, J. D. Weaver, A. M. Riley, R. Tyagi, et al. 2014. “Human Genome-Wide RNAi Screen Identifies an Essential Role for Inositol Pyrophosphates in Type-I Interferon Response.” PLoS Pathogens 10 (2): e1003981. doi:10.1371/journal.ppat.1003981. http://dx.doi.org/10.1371/journal.ppat.1003981.
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Abstract: The pattern recognition receptor RIG-I is critical for Type-I interferon production. However, the global regulation of RIG-I signaling is only partially understood. Using a human genome-wide RNAi-screen, we identified 226 novel regulatory proteins of RIG-I mediated interferon-β production. Furthermore, the screen identified a metabolic pathway that synthesizes the inositol pyrophosphate 1-IP7 as a previously unrecognized positive regulator of interferon production. Detailed genetic and biochemical experiments demonstrated that the kinase activities of IPPK, PPIP5K1 and PPIP5K2 (which convert IP5 to1-IP7) were critical for both interferon induction, and the control of cellular infection by Sendai and influenza A viruses. Conversely, ectopically expressed inositol pyrophosphate-hydrolases DIPPs attenuated interferon transcription. Mechanistic experiments in intact cells revealed that the expression of IPPK, PPIP5K1 and PPIP5K2 was needed for the phosphorylation and activation of IRF3, a transcription factor for interferon. The addition of purified individual inositol pyrophosphates to a cell free reconstituted RIG-I signaling assay further identified 1-IP7 as an essential component required for IRF3 activation. The inositol pyrophosphate may act by β-phosphoryl transfer, since its action was not recapitulated by a synthetic phosphonoacetate analogue of 1-IP7. This study thus identified several novel regulators of RIG-I, and a new role for inositol pyrophosphates in augmenting innate immune responses to viral infection that may have therapeutic applications.
Published Version: doi:10.1371/journal.ppat.1003981
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937324/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:12064389
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