IRE1β negatively regulates IRE1α signaling in response to endoplasmic reticulum stress

Grey, M. J.; Cloots, E.; Simpson, M. S.; LeDuc, N.; Serebrenik, Y.; De Luca, H.; De Sutter, D.; Luong, P.; Thiagarajah, J. R.; Paton, A. W.; Paton, J. C.; Seeliger, M.; Eyckerman, S.; Janssens, S.; Lencer, W. I.

doi:10.1101/586305

bioRxiv · 10.1101/586305

IRE1β negatively regulates IRE1α signaling in response to endoplasmic reticulum stress

Grey, M. J.·Cloots, E.·Simpson, M. S.·LeDuc, N.·Serebrenik, Y.·De Luca, H.·De Sutter, D.·Luong, P.·Thiagarajah, J. R.·Paton, A. W.·Paton, J. C.·Seeliger, M.·Eyckerman, S.·Janssens, S.·Lencer, W. I.

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Abstract

IRE1{beta} is an ER stress sensor uniquely expressed in epithelial cells lining mucosal surfaces. Here, we show that intestinal epithelial cells expressing IRE1{beta} have an attenuated response to ER stress. IRE1{beta} assembles with and blocks activation of the closely related and most evolutionarily ancient stress-sensor IRE1 to suppress stress-induced xbp1 splicing, a key mediator of the unfolded protein response. In comparison, IRE1{beta} has weak xbp1 splicing activity, largely explained by a non-conserved amino acid in the kinase domain that impairs its phosphorylation and restricts oligomerization. This enables IRE1{beta} to act as a dominant negative suppressor of IRE1. The inhibitory effect is amplified in cells by disrupting an XBP1-dependent feedback loop regulating stress-induced expression of IRE1. Thus IRE1{beta} functions to negatively regulate IRE1 signaling, perhaps enabling intestinal epithelial cells to manage the response to chronic stress stimuli at the host-environment interface.

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Grey, M. J., Cloots, E., Simpson, M. S., LeDuc, N., Serebrenik, Y., De Luca, H., De Sutter, D., Luong, P., Thiagarajah, J. R., Paton, A. W., Paton, J. C., Seeliger, M., Eyckerman, S., Janssens, S., Lencer, W. I.. 2019-03-23. IRE1β negatively regulates IRE1α signaling in response to endoplasmic reticulum stress. https://doi.org/10.1101/586305

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