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

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dc.contributor.authorYamazaki, H.
dc.contributor.authorHiramatsu, K.
dc.contributor.authorHayakawa, K.
dc.contributor.authorTagawa, Y.
dc.contributor.authorOkamura, M.
dc.contributor.authorOgata, R.
dc.contributor.authorHuang, T.
dc.contributor.authorNakajima, S.
dc.contributor.authorYao, J.
dc.contributor.authorPaton, A.
dc.contributor.authorPaton, J.
dc.contributor.authorKitamura, M.
dc.date.issued2009
dc.description.abstractShiga 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.
dc.description.statementofresponsibilityHiroaki Yamazaki, Nobuhiko Hiramatsu, Kunihiro Hayakawa, Yasuhiro Tagawa, Maro Okamura, Ryouji Ogata, Tao Huang, Shotaro Nakajima, Jian Yao, Adrienne W. Paton, James C. Paton and Masanori Kitamura
dc.identifier.citationJournal of Immunology, 2009; 183(2):1480-1487
dc.identifier.doi10.4049/jimmunol.0900017
dc.identifier.issn0022-1767
dc.identifier.issn1550-6606
dc.identifier.orcidPaton, J. [0000-0001-9807-5278]
dc.identifier.urihttp://hdl.handle.net/2440/57154
dc.language.isoen
dc.publisherAmer Assoc Immunologists
dc.source.urihttps://doi.org/10.4049/jimmunol.0900017
dc.subjectCell Line
dc.subjectEndoplasmic Reticulum
dc.subjectAnimals
dc.subjectRats
dc.subjectSubtilisins
dc.subjectEscherichia coli Proteins
dc.subjectNF-kappa B
dc.subjectHeat-Shock Proteins
dc.subjectMolecular Chaperones
dc.subjectCytotoxins
dc.subjectSignal Transduction
dc.subjectProtein Folding
dc.subjectPhosphorylation
dc.subjectProto-Oncogene Proteins c-akt
dc.subjectActivating Transcription Factor 6
dc.subjectEndoplasmic Reticulum Chaperone BiP
dc.titleActivation of the Akt-NF-kappa B Pathway by Subtilase Cytotoxin through the ATF6 Branch of the Unfolded Protein Response
dc.typeJournal article
pubs.publication-statusPublished

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