Human Genome-Wide RNAi Screen Identifies an Essential Role for Inositol Pyrophosphates in Type-I Interferon Response
View/ Open
Author
Pulloor, Niyas Kudukkil
Nair, Sajith
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.
Krishnan, Manoj N.
Note: Order does not necessarily reflect citation order of authors.
Published Version
https://doi.org/10.1371/journal.ppat.1003981Metadata
Show full item recordCitation
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.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.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#LAACitable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:12064389
Collections
- HMS Scholarly Articles [17918]
- SPH Scholarly Articles [6362]
Contact administrator regarding this item (to report mistakes or request changes)