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Human genome-wide RNAi screen identifies an essential role for inositol pyrophosphates in Type-I interferon response.

Publication ,  Journal Article
Pulloor, NK; Nair, S; McCaffrey, K; Kostic, AD; Bist, P; Weaver, JD; Riley, AM; Tyagi, R; Uchil, PD; York, JD; Snyder, SH; García-Sastre, A ...
Published in: PLoS Pathog
February 2014

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.

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Published In

PLoS Pathog

DOI

EISSN

1553-7374

Publication Date

February 2014

Volume

10

Issue

2

Start / End Page

e1003981

Location

United States

Related Subject Headings

  • Virology
  • Signal Transduction
  • Receptors, Retinoic Acid
  • RNA, Small Interfering
  • Phosphoric Monoester Hydrolases
  • Interferon Type I
  • Interferon Regulatory Factor-3
  • Immunity, Innate
  • Humans
  • Gene Expression Regulation
 

Citation

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Pulloor, N. K., Nair, S., McCaffrey, K., Kostic, A. D., Bist, P., Weaver, J. D., … Krishnan, M. N. (2014). Human genome-wide RNAi screen identifies an essential role for inositol pyrophosphates in Type-I interferon response. PLoS Pathog, 10(2), e1003981. https://doi.org/10.1371/journal.ppat.1003981
Pulloor, Niyas Kudukkil, Sajith Nair, Kathleen McCaffrey, Aleksandar D. Kostic, Pradeep Bist, Jeremy D. Weaver, Andrew M. Riley, et al. “Human genome-wide RNAi screen identifies an essential role for inositol pyrophosphates in Type-I interferon response.PLoS Pathog 10, no. 2 (February 2014): e1003981. https://doi.org/10.1371/journal.ppat.1003981.
Pulloor NK, Nair S, McCaffrey K, Kostic AD, Bist P, Weaver JD, et al. Human genome-wide RNAi screen identifies an essential role for inositol pyrophosphates in Type-I interferon response. PLoS Pathog. 2014 Feb;10(2):e1003981.
Pulloor, Niyas Kudukkil, et al. “Human genome-wide RNAi screen identifies an essential role for inositol pyrophosphates in Type-I interferon response.PLoS Pathog, vol. 10, no. 2, Feb. 2014, p. e1003981. Pubmed, doi:10.1371/journal.ppat.1003981.
Pulloor NK, Nair S, McCaffrey K, Kostic AD, Bist P, Weaver JD, Riley AM, Tyagi R, Uchil PD, York JD, Snyder SH, García-Sastre A, Potter BVL, Lin R, Shears SB, Xavier RJ, Krishnan MN. Human genome-wide RNAi screen identifies an essential role for inositol pyrophosphates in Type-I interferon response. PLoS Pathog. 2014 Feb;10(2):e1003981.

Published In

PLoS Pathog

DOI

EISSN

1553-7374

Publication Date

February 2014

Volume

10

Issue

2

Start / End Page

e1003981

Location

United States

Related Subject Headings

  • Virology
  • Signal Transduction
  • Receptors, Retinoic Acid
  • RNA, Small Interfering
  • Phosphoric Monoester Hydrolases
  • Interferon Type I
  • Interferon Regulatory Factor-3
  • Immunity, Innate
  • Humans
  • Gene Expression Regulation