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B Pathway by Subtilase Cytotoxin through the ATF6 Branch of the Unfolded Protein Response1
* Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan; and
School of Molecular and Biomedical Science, University of Adelaide, South Australia, Australia
Shiga toxin has the potential to induce expression of inflammation-associated genes, although the underlying mechanisms are not well understood. We examined the effects of subtilase cytotoxin (SubAB), an AB5 toxin produced by some Shiga toxigenic Escherichia coli, on the activation of NF-
B. SubAB is known to be a protease which selectively degrades GRP78/Bip. Treatment of NRK-52E cells with SubAB caused rapid cleavage of GRP78. Following the degradation of GRP78, transient activation of NF-B was observed with a peak at 6–12 h; the activation subsided within 24 h despite the continuous absence of intact GRP78. The activation of NF-B was preceded by transient phosphorylation of Akt. Treatment of the cells with a selective inhibitor of Akt1/2 or an inhibitor of PI3K attenuated SubAB-induced NF-B activation, suggesting that activation of Akt is an event upstream of NF-B. Degradation of GRP78 caused the unfolded protein response (UPR), and inducers of the UPR mimicked the stimulatory effects of SubAB on Akt and NF-B. SubAB triggered the three major branches of the UPR including the IRE1-XBP1, PERK, and ATF6 pathways. Dominant-negative inhibition of IRE1
, XBP1, or PERK did not attenuate activation of NF-B by SubAB. In contrast, genetic and pharmacological inhibition of ATF6 significantly suppressed SubAB-triggered Akt phosphorylation and NF-B activation. These results suggested that loss of GRP78 by SubAB leads to transient phosphorylation of Akt and consequent activation of NF-B through the ATF6 branch of the UPR.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported, in part, by Grant-in-Aids for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (No.16390243, No.17651026, No.19651024; to M.K.), and by Grant No. R01AI-068715 from the National Institutes of Health (to A.W.P. and J.C.P.).
2 H.Y. and N.H. equally contributed to this work.
3 Address correspondence and reprint requests to Masanori Kitamura, Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Shimokato 1110, Chuo, Yamanashi 409-3898, Japan. E-mail address: masanori{at}yamanashi.ac.jp
4 Abbreviations used in this paper: HUS, hemolytic uremic syndrome; SubAB, subtilase cytotoxin; GRP78, 78 kDa glucose-regulated protein; ER, endoplasmic reticulum; UPR, unfolded protein response; ATF6, activating transcription factor 6; AEBSF, 4-(2-aminoethyl)benzenesulfonyl fluoride; SEAP, secreted alkaline phosphatase; MEF, mouse embryonic fibroblasts; UPRE, UPR element; DN, dominant-negative mutant; IRE1, inositol-requiring ER-to-nucleus signal kinase 1; XBP1, X-box binding protein 1; PERK, RNA-dependent protein kinase-like ER kinase; eIF2, eukaryotic translation initiation factor 2; IKK, IB kinase; TRAF2, TNF-associated factor 2.
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