HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) All Versions of this Article: jimmunol.0900017v1 183/2/1480    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Google Scholar Articles by Yamazaki, H. Articles by Kitamura, M. PubMed PubMed Citation Articles by Yamazaki, H. Articles by Kitamura, M. Pubmed/NCBI databases Substance via MeSH

Activation of the Akt-NF-B Pathway by Subtilase Cytotoxin through the ATF6 Branch of the Unfolded Protein Response¹

Hiroaki Yamazaki^2,*, Nobuhiko Hiramatsu^2,*, Kunihiro Hayakawa^*, Yasuhiro Tagawa^*, Maro Okamura^*, Ryouji Ogata^*, Tao Huang^*, Shotaro Nakajima^*, Jian Yao^*, Adrienne W. Paton, James C. Paton and Masanori Kitamura^3,*

*Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan; 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.

³Address 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

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.).

²H.Y. and N.H. equally contributed to this work.

This article has been cited by other articles:

				M. Kitamura Endoplasmic Reticulum Stress in Glomerulonephritis: The Bad Guy Turns Good? J. Am. Soc. Nephrol., September 1, 2009; 20(9): 1871 - 1873. [Full Text] [PDF]