E3 ubiquitin ligase Cbl‐b suppresses human ORMDL3 expression through STAT6 mediation

Yang, Weiyou; Jin, Rui; Jiang, Chunming; Wang, Xiaohua; Shu, Jin; Li, Ling; Zhu, Liang‐Hua; Zhuang, Lili; Gao, Chao; Zhou, Guoping

doi:10.1016/j.febslet.2015.06.015

Cited by 6 publications

(6 citation statements)

References 31 publications

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“…Second, ORMDL3 regulates airway remodeling through ATF6 and its downstream gene SERCA2b [9, 10]. Finally, one study from our own group has shown that ubiquitin ligase Cbl-b inhibits human ORMDL3 expression through STAT6 [36]. To summarize these previous studies, it is an obvious question whether the ORMDL3/ATF6 regulatory axis plays a role in insulin demand-induced beta cell proliferation, which was addressed here, where we focused on the initial activation of UPR and associated proteins ORMDL3 and ATF6 in a pro-diabetic environment, using 3 days’ culture in high glucose.…”

Section: Discussionmentioning

confidence: 99%

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The role of ORMDL3/ATF6 in compensated beta cell proliferation during early diabetes

Yang

Sheng

Sun

et al. 2019

Aging

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Endoplasmic reticulum (ER) stress in beta cells induces a signaling network called the unfolded protein response (UPR), which plays a dual role in diabetes. A key regulator of ER-stress and UPR, the orosomucoid 1-like protein 3 (ORMDL3), has been shown to regulate airway remodeling through a major UPR protein, activating transcription factor 6 (ATF6), but the contribution of this regulatory axis to compensatory pancreatic beta cell proliferation in diabetes has not been studied. Here, we detected significantly lower levels of ORMDL3 mRNA in leukocytes of peripheral blood specimens from type 1 diabetes (T1D) children, compared to normal children. Moreover, these ORMDL3 levels in T1D children exhibited further decreases upon follow-up. ORMDL3 levels in islets from NOD mice, a mouse model for T1D in humans, showed a mild increase before diabetes onset, but a gradual decrease subsequently. In high glucose culture, beta cell proliferation, but not apoptosis, was increased by overexpression of ORMDL3 levels, likely mediated by its downstream factor ATF6. Mechanistically, ORMDL3 transcriptionally activated ATF6, which was confirmed in a promoter reporter assay. Together, our data suggest that ORMDL3 may increase beta cell proliferation through ATF6 as an early compensatory change in response to diabetes.

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Section: Discussionmentioning

confidence: 99%

“…Western blotting was performed as previously described [36]. Primary antibodies for Western blot are rabbit anti-GAPDH (1:1000; Cell signaling, San Jose, CA, USA; Catalog number: #2118), rabbit anti-ORMDL3 (1:500; Abcam; Catalog number: ab107639), and rabbit anti-ATF6 (1: 1000; Cell signaling; Catalog number: #65880).…”

Section: Methodsmentioning

confidence: 99%

The role of ORMDL3/ATF6 in compensated beta cell proliferation during early diabetes

Yang

Sheng

Sun

et al. 2019

Aging

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“…They further noted that while IL‐4 could stimulate the phosphorylation of STAT6, Cbl‐b could downregulate the level of p‐STAT6. This work revealed a possible mechanism in which Cbl‐b, an upstream regulator, could passively modulate the expression of ORMDL3 by inhibiting the phosphorylation of STAT6 …”

Section: Cbl‐bmentioning

confidence: 91%

ORMDL3 and its implication in inflammatory disorders

Long

Yun

et al. 2018

Int J of Rheum Dis

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A growing body of evidence has suggested the genetic association of ORMDL3 gene (ORMDL Sphingolipid Biosynthesis Regulator 3) polymorphisms with a diverse set of inflammatory disorders that include bronchial asthma, inflammatory bowel disease, ankylosing spondylitis and atherosclerosis. Gene functional investigations have revealed the particular relevance of ORMDL3 in endoplasmic reticulum stress, lipid metabolism and inflammatory reactions. Additionally, several reports have recently added a new dimension to our understanding of the modulation of ORMDL3 gene expression in inflammation. This mini-review summarizes the pertinent publications regarding the genetic association studies and mechanistic exploration of ORMDL3 in common inflammatory disorders.

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“…A recent parallel study described the significant elevation of orosomucoid 1‐like protein 3 (ORMDL3) expression, while Cbl‐b expression was down‐regulated in patients with recurrent wheeze compared to healthy subjects. These data documented that ORMDL3 expression is controlled by Cbl‐b, which targets the STAT‐6 for ubiquitination and subsequent degradation via phosphorylation [126].…”

Section: Cbl‐b In Immune‐related Diseasesmentioning

confidence: 99%

“…Cbl‐b −/− T cells are partially resistant to T reg cell‐mediated suppression and unable to develop T cell anergy [126]. It is well established that maintaining the expression of FoxP3 in T regs is dependent upon Cbl‐b [36].…”

Section: Cbl‐b In Immune‐related Diseasesmentioning

confidence: 99%

E3 ubiquitin ligase Casitas B lineage lymphoma-b and its potential therapeutic implications for immunotherapy

Jafari

Mousavi

Shahbaz

et al. 2021

Clinical and Experimental Immunology

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Summary The distinction of self from non‐self is crucial to prevent autoreactivity and ensure protection from infectious agents and tumors. Maintaining the balance between immunity and tolerance of immune cells is strongly controlled by several sophisticated regulatory mechanisms of the immune system. Among these, the E3 ligase ubiquitin Casitas B cell lymphoma‐b (Cbl‐b) is a newly identified component in the ubiquitin‐dependent protein degradation system, which is thought to be an important negative regulator of immune cells. An update on the current knowledge and new concepts of the relevant immune homeostasis program co‐ordinated by Cbl‐b in different cell populations could pave the way for future immunomodulatory therapies of various diseases, such as autoimmune and allergic diseases, infections, cancers and other immunopathological conditions. In the present review, the latest findings are comprehensively summarized on the molecular structural basis of Cbl‐b and the suppressive signaling mechanisms of Cbl‐b in physiological and pathological immune responses, as well as its emerging potential therapeutic implications for immunotherapy in animal models and human diseases.

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E3 ubiquitin ligase Cbl‐b suppresses human ORMDL3 expression through STAT6 mediation

Cited by 6 publications

References 31 publications

The role of ORMDL3/ATF6 in compensated beta cell proliferation during early diabetes

The role of ORMDL3/ATF6 in compensated beta cell proliferation during early diabetes

ORMDL3 and its implication in inflammatory disorders

E3 ubiquitin ligase Casitas B lineage lymphoma-b and its potential therapeutic implications for immunotherapy

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