Interleukin-1 Receptor-Associated Kinase-2 (IRAK2) Is a Critical Mediator of Endoplasmic Reticulum (ER) Stress Signaling

Samir Benosman, Palaniyandi Ravanan, Ricardo G. Correa, Ying Chen Hou, Minjia Yu, Muhammet Fatih Gulen, Xiaoxia Li, James Thomas, Michael Cuddy, Yasuko Matsuzawa, Renata Sano, Paul Diaz, Shu ichi Matsuzawa, John C. Reed

Research output: Contribution to journalArticle

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Abstract

Endoplasmic reticulum (ER) stress occurs when unfolded proteins accumulate in the lumen of the organelle, triggering signal transduction events that contribute either to cellular adaptation and recovery or alternatively to cellular dysfunction and death. ER stress has been implicated in numerous diseases. To identify novel modulators of ER stress, we undertook a siRNA library screen of the kinome, revealing Interleukin-1 Receptor-Associated Kinase-2 (IRAK2) as a contributor to unfolded protein response (UPR) signaling and ER stress-induced cell death. Knocking down expression of IRAK2 (but not IRAK1) in cultured mammalian cells suppresses ER stress-induced expression of the pro-apoptotic transcription factor CHOP and activation of stress kinases. Similarly, RNAi-mediated silencing of the IRAK family member Tube (but not Pelle) suppresses activation of stress kinase signaling induced by ER stress in Drosophila cells. The action of IRAK2 maps to the IRE1 pathway, rather than the PERK or ATF6 components of the UPR. Interestingly, ER stress also induces IRAK2 gene expression in an IRE1/XBP1-dependent manner, suggesting a mutually supporting amplification loop involving IRAK2 and IRE1. In vivo, ER stress induces Irak2 expression in mice. Moreover, Irak2 gene knockout mice display defects in ER stress-induced CHOP expression and IRE1 pathway signaling. These findings demonstrate an unexpected linkage of the innate immunity machinery to UPR signaling, revealing IRAK2 as a novel amplifier of the IRE1 pathway.

Original languageEnglish (US)
Article numbere64256
JournalPLoS One
Volume8
Issue number5
DOIs
StatePublished - May 28 2013

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Interleukin-1 Receptor-Associated Kinases
Endoplasmic Reticulum Stress
interleukin-1
endoplasmic reticulum
phosphotransferases (kinases)
receptors
unfolded protein response
Unfolded Protein Response
Phosphotransferases
Transcription Factor CHOP
Proteins
Protein Unfolding
Gene Knockout Techniques
Chemical activation
mice
gene targeting
transcriptional activation
small interfering RNA
RNA Interference
Signal transduction

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Benosman, S., Ravanan, P., Correa, R. G., Hou, Y. C., Yu, M., Gulen, M. F., ... Reed, J. C. (2013). Interleukin-1 Receptor-Associated Kinase-2 (IRAK2) Is a Critical Mediator of Endoplasmic Reticulum (ER) Stress Signaling. PLoS One, 8(5), [e64256]. https://doi.org/10.1371/journal.pone.0064256

Interleukin-1 Receptor-Associated Kinase-2 (IRAK2) Is a Critical Mediator of Endoplasmic Reticulum (ER) Stress Signaling. / Benosman, Samir; Ravanan, Palaniyandi; Correa, Ricardo G.; Hou, Ying Chen; Yu, Minjia; Gulen, Muhammet Fatih; Li, Xiaoxia; Thomas, James; Cuddy, Michael; Matsuzawa, Yasuko; Sano, Renata; Diaz, Paul; Matsuzawa, Shu ichi; Reed, John C.

In: PLoS One, Vol. 8, No. 5, e64256, 28.05.2013.

Research output: Contribution to journalArticle

Benosman, S, Ravanan, P, Correa, RG, Hou, YC, Yu, M, Gulen, MF, Li, X, Thomas, J, Cuddy, M, Matsuzawa, Y, Sano, R, Diaz, P, Matsuzawa, SI & Reed, JC 2013, 'Interleukin-1 Receptor-Associated Kinase-2 (IRAK2) Is a Critical Mediator of Endoplasmic Reticulum (ER) Stress Signaling', PLoS One, vol. 8, no. 5, e64256. https://doi.org/10.1371/journal.pone.0064256
Benosman, Samir ; Ravanan, Palaniyandi ; Correa, Ricardo G. ; Hou, Ying Chen ; Yu, Minjia ; Gulen, Muhammet Fatih ; Li, Xiaoxia ; Thomas, James ; Cuddy, Michael ; Matsuzawa, Yasuko ; Sano, Renata ; Diaz, Paul ; Matsuzawa, Shu ichi ; Reed, John C. / Interleukin-1 Receptor-Associated Kinase-2 (IRAK2) Is a Critical Mediator of Endoplasmic Reticulum (ER) Stress Signaling. In: PLoS One. 2013 ; Vol. 8, No. 5.
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