title: Interleukin-1 receptor-associated kinase-2 (IRAK2) is a critical mediator of endoplasmic reticulum (ER) stress signaling.
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.
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Samir
authors.initials: S
authors.lastname: Benosman
authors.forename: Palaniyandi
authors.initials: P
authors.lastname: Ravanan
authors.forename: Ricardo G
authors.initials: RG
authors.lastname: Correa
authors.forename: Ying-Chen
authors.initials: YC
authors.lastname: Hou
authors.forename: Minjia
authors.initials: M
authors.lastname: Yu
authors.forename: Muhammet Fatih
authors.initials: MF
authors.lastname: Gulen
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
authors.forename: James
authors.initials: J
authors.lastname: Thomas
authors.forename: Michael
authors.initials: M
authors.lastname: Cuddy
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Matsuzawa
authors.forename: Renata
authors.initials: R
authors.lastname: Sano
authors.forename: Paul
authors.initials: P
authors.lastname: Diaz
authors.forename: Shu-ichi
authors.initials: S
authors.lastname: Matsuzawa
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
mesh_terms: D000818:Animals; D016923:Cell Death; D002460:Cell Line; D004330:Drosophila / Q000166:cytology; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D056811:Unfolded Protein Response
chemical_list: D008565:Membrane Proteins; D034741:RNA, Small Interfering; C486556:Ern2 protein, mouse; D053592:Interleukin-1 Receptor-Associated Kinases; D017346:Protein Serine-Threonine Kinases