1. The IRE1/Xbp1 axis restores ER and tissue homeostasis perturbed by excess Notch in Drosophila.
- Author
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Li Y, Liu D, Wang H, Zhang X, Lu B, and Li S
- Subjects
- Animals, Humans, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Endoplasmic Reticulum metabolism, Endoplasmic Reticulum Stress genetics, Endoribonucleases genetics, Endoribonucleases metabolism, Homeostasis, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism, Receptors, Notch genetics, Receptors, Notch metabolism, Unfolded Protein Response, Drosophila metabolism, Drosophila Proteins genetics, Drosophila Proteins metabolism
- Abstract
Notch signaling controls numerous key cellular processes including cell fate determination and cell proliferation. Its malfunction has been linked to many developmental abnormalities and human disorders. Overactivation of Notch signaling is shown to be oncogenic. Retention of excess Notch protein in the endoplasmic reticulum (ER) can lead to altered Notch signaling and cell fate, but the mechanism is not well understood. In this study, we show that V5-tagged or untagged exogenous Notch is retained in the ER when overexpressed in fly tissues. Furthermore, we show that Notch retention in the ER leads to robust ER enlargement and elicits a rough eye phenotype. Gain-of-function of unfolded protein response (UPR) factors IRE1 or spliced Xbp1 (Xbp1-s) alleviates Notch accumulation in the ER, restores ER morphology and ameliorates the rough eye phenotype. Our results uncover a pivotal role of the IRE1/Xbp1 axis in regulating the detrimental effect of ER-localized excess Notch protein during development and tissue homeostasis., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2024
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