Integration of UPR and Oxidative Stress Signaling in the Control of Intestinal Stem Cell Proliferation

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Loss of proper protein homeostasis (proteostasis) as well as increased production of reactive oxygen species (ROS) is a hallmark of aging. In complex metazoans, these processes can result in proliferative diseases and cancers. The protein folding capacity of the endoplasmic reticulum (ER) is monitored and maintained by the unfolded protein response of the ER (UPRER). In this study, we identify a coordinated role of UPRER and oxidative stress signaling in regulating the proliferation of intestinal stem cells (ISCs). We find that the ER-stress responsive transcription factor Xbp1 and the ER-associated degradation pathway component Hrd1 are sufficient and required cell autonomously in ISCs to limit their proliferative activity. This function is dependent on the activities of the stress sensor JNK and the redox-responsive transcription factor CncC, which we have previously identified as regulators of ISC proliferation. We further show here that promoting ER homeostasis in aging ISCs is sufficient to limit age-associated epithelial dysplasia. Our results establish the integration of UPRER and oxidative stress signaling as a central mechanism promoting regenerative homeostasis in the intestinal epithelium.

Vyšlo v časopise: Integration of UPR and Oxidative Stress Signaling in the Control of Intestinal Stem Cell Proliferation. PLoS Genet 10(8): e32767. doi:10.1371/journal.pgen.1004568
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004568

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