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Published online
doi:10.1083/jcb.200704166
The Journal of Cell Biology, Vol. 179, No. 1, 75-86
The Rockefeller University Press, 0021-9525 $30.00
© Kimata et al.
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Article

Two regulatory steps of ER-stress sensor Ire1 involving its cluster formation and interaction with unfolded proteins



Yukio Kimata1, Yuki Ishiwata-Kimata1, Tatsuhiko Ito1, Aiko Hirata2, Tomohide Suzuki1, Daisuke Oikawa1, Masato Takeuchi1, and Kenji Kohno1

1 Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Nara 630-0192, Japan
2 Department of Integrated Biosciences, Graduate School of Frontier Sciences, the University of Tokyo, Kashiwa, Chiba 277-8562, Japan

Correspondence to Yukio Kimata: kimata{at}zero.ad.jp; or Kenji Kohno: kkouno{at}bs.naist.jp

Chaperone protein BiP binds to Ire1 and dissociates in response to endoplasmic reticulum (ER) stress. However, it remains unclear how the signal transducer Ire1 senses ER stress and is subsequently activated. The crystal structure of the core stress-sensing region (CSSR) of yeast Ire1 luminal domain led to the controversial suggestion that the molecule can bind to unfolded proteins. We demonstrate that, upon ER stress, Ire1 clusters and actually interacts with unfolded proteins. Ire1 mutations that affect these phenomena reveal that Ire1 is activated via two steps, both of which are ER stress regulated, albeit in different ways. In the first step, BiP dissociation from Ire1 leads to its cluster formation. In the second step, direct interaction of unfolded proteins with the CSSR orients the cytosolic effector domains of clustered Ire1 molecules.

Abbreviations used in this paper: CSSR, core stress-sensing region; IP, immunoprecipitate; MBP, maltose binding protein; MHC, major histocompatibility complex; PERK, pancreatic ER kinase; Tun, Tunicamycin; UPR, unfolded protein response; UPRE, UPR element.


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