Glucocorticoids alleviate intestinal ER stress by enhancing protein folding and degradation of misfolded proteins

Das, Indrajit; Png, Chin Wen; Oancea, Iulia; Hasnain, Sumaira Z.; Lourie, Rohan; Proctor, Martina; Eri, Rajaraman; Sheng, Yong; Crane, Denis I.; Florin, Timothy H.; McGuckin, Michael A.

doi:10.1083/jcb2014oia7

Cited by 6 publications

(8 citation statements)

References 29 publications

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“…Immunoregulatory properties have been assigned to this extra-adrenal source of GCs, such as modulation of intestinal T lymphocyte activation upon viral infection,16 or suppression of T cell activation and apoptosis promotion 19. Recently, endogenous GCs have been shown to alleviate endoplasmic reticulum stress that triggers and maintains inflammation in patients with active IBD 27 28. However, none of these studies described cortisol production in humans and the impact of its deficiency in epithelial cells in UC specimens.…”

Section: Discussionmentioning

confidence: 99%

Intestinal steroidogenesis controls PPARγ expression in the colon and is impaired during ulcerative colitis

Bouguen

Langlois

Djouina

et al. 2014

Gut

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Section: Discussionmentioning

confidence: 99%

Intestinal steroidogenesis controls PPARγ expression in the colon and is impaired during ulcerative colitis

Bouguen

Langlois

Djouina

et al. 2014

Gut

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“…Although previous studies have reported protective roles for glucocorticoids in cell death, [61][62][63] our current study characterizes a role for transrepression and not transactivation in the glucocorticoid-mediated protection against ER stress-induced apoptosis (Figure 3). Notably, we have identified, characterized and validated a role of GDF15 in ER stress-induced apoptosis (Figure 4).…”

Section: Discussionmentioning

confidence: 79%

The transrepression arm of glucocorticoid receptor signaling is protective in mutant huntingtin-mediated neurodegeneration

et al. 2015

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The unfolded protein response (UPR) occurs following the accumulation of unfolded proteins in the endoplasmic reticulum (ER) and orchestrates an intricate balance between its prosurvival and apoptotic arms to restore cellular homeostasis and integrity. However, in certain neurodegenerative diseases, the apoptotic arm of the UPR is enhanced, resulting in excessive neuronal cell death and disease progression, both of which can be overcome by modulating the UPR. Here, we describe a novel crosstalk between glucocorticoid receptor signaling and the apoptotic arm of the UPR, thus highlighting the potential of glucocorticoid therapy in treating neurodegenerative diseases. Several glucocorticoids, but not mineralocorticoids, selectively antagonize ER stress-induced apoptosis in a manner that is downstream of and/or independent of the conventional UPR pathways. Using GRT10, a novel selective pharmacological modulator of glucocorticoid signaling, we describe the importance of the transrepression arm of the glucocorticoid signaling pathway in protection against ER stress-induced apoptosis. Furthermore, we also observe the protective effects of glucocorticoids in vivo in a Drosophila model of Huntington's disease (HD), wherein treatment with different glucocorticoids diminished rhabdomere loss and conferred neuroprotection. Finally, we find that growth differentiation factor 15 has an important role downstream of glucocorticoid signaling in antagonizing ER stress-induced apoptosis in cells, as well as in preventing HD-mediated neurodegeneration in flies. Thus, our studies demonstrate that this novel crosstalk has the potential to be effectively exploited in alleviating several neurodegenerative disorders.

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“…In the intestine dis regulation of normal ER responses are particularly sensitive since dysfunction of UPR leads to spontaneous colitis in rodents lacking the transcription factor XBP1 (X box binding protein 1), involved in protein load [70,71]. In Winnie mice with increased intestinal ER stress caused by a missense mutation of the Muc2 mucin gene, GCs suppress ER stress and activation of the UPR in a glucocorticoid receptor dependent manner [72]. GCs promote correct folding of secreted proteins and facilitate the enhanced removal of misfolded proteins from the ER through up regulation of genes encoding chaperones and elements of ER associated degradation (ERAD) [72].…”

Section: Other Properties Of Intestinal Gcsmentioning

confidence: 99%

“…The steroidogenesis state in patients with CD is not yet known. Since GCs are able to relieve the ER stress [72], UPR are more likely to be impaired in UC patients with defective IEC synthesis of cortisol.…”

Section: Inflammatory Bowel Diseasesmentioning

confidence: 99%

“…In Winnie mice with increased intestinal ER stress caused by a missense mutation of the Muc2 mucin gene, GCs suppress ER stress and activation of the UPR in a glucocorticoid receptor dependent manner [72]. GCs promote correct folding of secreted proteins and facilitate the enhanced removal of misfolded proteins from the ER through up regulation of genes encoding chaperones and elements of ER associated degradation (ERAD) [72]. These results suggest that epithelial steroidogenesis may also influence gut homeostasis by modulating ER responses in response to exogenous and endogenous stresses.…”

Section: Other Properties Of Intestinal Gcsmentioning

confidence: 99%

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Intestinal steroidogenesis

et al. 2015

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a b s t r a c tSteroids are fundamental hormones that control a wide variety of physiological processes such as metabolism, immune functions, and sexual characteristics. Historically, steroid synthesis was considered a function restricted to the adrenals and the gonads. In the past 20 years, a significant number of studies have demonstrated that steroids could also be synthesized or metabolized by other organs. According to these studies, the intestine appears to be a major source of de novo produced glucocorticoids as well as a tissue capable of producing and metabolizing sex steroids. This finding is based on the detection of ste roidogenic enzyme expression as well as the presence of bioactive steroids in both the rodent and human gut. Within the intestinal mucosa, the intestinal epithelial cell layer is one of the main cellular sources of steroids. Glucocorticoid synthesis regulation in the intestinal epithelial cells is unique in that it does not involve the classical positive regulator steroidogenic factor 1 (SF 1) but a closely related homolog, namely the liver receptor homolog 1 (LRH 1). This local production of immunoregulatory glucocorticoids contributes to intestinal homeostasis and has been linked to pathophysiology of inflammatory bowel dis eases. Intestinal epithelial cells also possess the ability to metabolize sex steroids, notably estrogen; this mechanism may impact colorectal cancer development. In this review, we contextualize and discuss what is known about intestinal steroidogenesis and regulation as well as the key role these functions play both in physiological and pathological conditions.

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Glucocorticoids alleviate intestinal ER stress by enhancing protein folding and degradation of misfolded proteins

Cited by 6 publications

References 29 publications

Intestinal steroidogenesis controls PPARγ expression in the colon and is impaired during ulcerative colitis

Intestinal steroidogenesis controls PPARγ expression in the colon and is impaired during ulcerative colitis

The transrepression arm of glucocorticoid receptor signaling is protective in mutant huntingtin-mediated neurodegeneration

Intestinal steroidogenesis

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