BiP binding to the ER-stress sensor Ire1 tunes the homeostatic behavior of the unfolded protein response.

The unfolded protein response (UPR) is an intracellular signaling pathway that counteracts variable stresses that impair protein folding in the endoplasmic reticulum (ER). As such, the UPR is thought to be a homeostat that finely tunes ER protein folding capacity and ER abundance according to need....

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Autores principales:	David Pincus, Michael W Chevalier, Tomás Aragón, Eelco van Anken, Simon E Vidal, Hana El-Samad, Peter Walter
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/cbb41832bd1649f09f05cfe7cc1394ad
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spelling	oai:doaj.org-article:cbb41832bd1649f09f05cfe7cc1394ad2021-12-02T19:54:46ZBiP binding to the ER-stress sensor Ire1 tunes the homeostatic behavior of the unfolded protein response.1544-91731545-788510.1371/journal.pbio.1000415https://doaj.org/article/cbb41832bd1649f09f05cfe7cc1394ad2010-07-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20625545/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885The unfolded protein response (UPR) is an intracellular signaling pathway that counteracts variable stresses that impair protein folding in the endoplasmic reticulum (ER). As such, the UPR is thought to be a homeostat that finely tunes ER protein folding capacity and ER abundance according to need. The mechanism by which the ER stress sensor Ire1 is activated by unfolded proteins and the role that the ER chaperone protein BiP plays in Ire1 regulation have remained unclear. Here we show that the UPR matches its output to the magnitude of the stress by regulating the duration of Ire1 signaling. BiP binding to Ire1 serves to desensitize Ire1 to low levels of stress and promotes its deactivation when favorable folding conditions are restored to the ER. We propose that, mechanistically, BiP achieves these functions by sequestering inactive Ire1 molecules, thereby providing a barrier to oligomerization and activation, and a stabilizing interaction that facilitates de-oligomerization and deactivation. Thus BiP binding to or release from Ire1 is not instrumental for switching the UPR on and off as previously posed. By contrast, BiP provides a buffer for inactive Ire1 molecules that ensures an appropriate response to restore protein folding homeostasis to the ER by modulating the sensitivity and dynamics of Ire1 activity.David PincusMichael W ChevalierTomás AragónEelco van AnkenSimon E VidalHana El-SamadPeter WalterPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 8, Iss 7, p e1000415 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 David Pincus Michael W Chevalier Tomás Aragón Eelco van Anken Simon E Vidal Hana El-Samad Peter Walter BiP binding to the ER-stress sensor Ire1 tunes the homeostatic behavior of the unfolded protein response.
description	The unfolded protein response (UPR) is an intracellular signaling pathway that counteracts variable stresses that impair protein folding in the endoplasmic reticulum (ER). As such, the UPR is thought to be a homeostat that finely tunes ER protein folding capacity and ER abundance according to need. The mechanism by which the ER stress sensor Ire1 is activated by unfolded proteins and the role that the ER chaperone protein BiP plays in Ire1 regulation have remained unclear. Here we show that the UPR matches its output to the magnitude of the stress by regulating the duration of Ire1 signaling. BiP binding to Ire1 serves to desensitize Ire1 to low levels of stress and promotes its deactivation when favorable folding conditions are restored to the ER. We propose that, mechanistically, BiP achieves these functions by sequestering inactive Ire1 molecules, thereby providing a barrier to oligomerization and activation, and a stabilizing interaction that facilitates de-oligomerization and deactivation. Thus BiP binding to or release from Ire1 is not instrumental for switching the UPR on and off as previously posed. By contrast, BiP provides a buffer for inactive Ire1 molecules that ensures an appropriate response to restore protein folding homeostasis to the ER by modulating the sensitivity and dynamics of Ire1 activity.
format	article
author	David Pincus Michael W Chevalier Tomás Aragón Eelco van Anken Simon E Vidal Hana El-Samad Peter Walter
author_facet	David Pincus Michael W Chevalier Tomás Aragón Eelco van Anken Simon E Vidal Hana El-Samad Peter Walter
author_sort	David Pincus
title	BiP binding to the ER-stress sensor Ire1 tunes the homeostatic behavior of the unfolded protein response.
title_short	BiP binding to the ER-stress sensor Ire1 tunes the homeostatic behavior of the unfolded protein response.
title_full	BiP binding to the ER-stress sensor Ire1 tunes the homeostatic behavior of the unfolded protein response.
title_fullStr	BiP binding to the ER-stress sensor Ire1 tunes the homeostatic behavior of the unfolded protein response.
title_full_unstemmed	BiP binding to the ER-stress sensor Ire1 tunes the homeostatic behavior of the unfolded protein response.
title_sort	bip binding to the er-stress sensor ire1 tunes the homeostatic behavior of the unfolded protein response.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/cbb41832bd1649f09f05cfe7cc1394ad
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BiP binding to the ER-stress sensor Ire1 tunes the homeostatic behavior of the unfolded protein response.

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