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Title: Human Genome-Wide RNAi Screen Identifies an Essential Role for Inositol Pyrophosphates in Type-I Interferon Response
Authors: Pulloor, N.K. 
Nair, S. 
Kostic, A.D.
Bist, P.
Weaver, J.D.
Riley, A.M.
Tyagi, R.
Uchil, P.D.
York, J.D.
Snyder, S.H.
García-Sastre, A.
Potter, B.V.L.
Lin, R.
Shears, S.B.
Xavier, R.J.
Krishnan, M.N. 
Issue Date: Feb-2014
Source: Pulloor, N.K., Nair, S., Kostic, A.D., Bist, P., Weaver, J.D., Riley, A.M., Tyagi, R., Uchil, P.D., York, J.D., Snyder, S.H., García-Sastre, A., Potter, B.V.L., Lin, R., Shears, S.B., Xavier, R.J., Krishnan, M.N. (2014-02). Human Genome-Wide RNAi Screen Identifies an Essential Role for Inositol Pyrophosphates in Type-I Interferon Response. PLoS Pathogens 10 (2) : -. ScholarBank@NUS Repository.
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.
Source Title: PLoS Pathogens
ISSN: 15537366
DOI: 10.1371/journal.ppat.1003981
Appears in Collections:Staff Publications

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