scholarly journals Suppressive role of E3 ubiquitin ligase FBW7 in type I diabetes in non-obese diabetic mice through mediation of ubiquitination of EZH2

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yingxue Guo ◽  
Junfeng Li ◽  
Shuang Fan ◽  
Qibo Hu
Keyword(s):  
Beta Cells ◽  
Ubiquitin Ligase ◽  
Pancreatic Beta Cells ◽  
Type I Diabetes ◽  
E3 Ubiquitin Ligase ◽  
Nod Mice ◽  
Beta Cell Apoptosis ◽  
Type I ◽  
Immunoprecipitation Assay ◽  
The Stability

AbstractThe current study tried to uncover the molecular mechanism of E3 ubiquitin ligase F-box and WD repeat domain-containing 7 (FBW7) in a heritable autoimmune disease, type I diabetes (T1D). After streptozotocin-induced T1D model establishment in non-obese diabetic (NOD) mouse, the protein expression of FBW7, enhancer of zeste homolog 2 (EZH2), and Zinc finger and BTB domain containing 16 (ZBTB16) was quantified. Next, splenocytes and pancreatic beta cells were isolated to measure the production of pro-inflammatory cytokines in splenocytes, as well as islet beta-cell apoptosis. Additionally, the stability of EZH2 induced by FBW7 was analyzed by cycloheximide chase assay. The binding affinity of FBW7 and EZH2 and the consequence of ubiquitination were monitored by co-immunoprecipitation assay. Last, a chromatin immunoprecipitation assay was employed to analyze the accumulation of EZH2 and H3K27me3 at the ZBTB16 promoter region. Our study demonstrated downregulated FBW7 and ZBTB16 and upregulated EZH2 in diabetic NOD mice. Overexpression of FBW7 in the NOD mice inhibited pro-inflammatory cytokine release in the splenocytes and the apoptosis of islets beta cells. FBW7 destabilized EZH2 and accelerated ubiquitin-dependent degradation. EZH2 and H3K27me3 downregulated the ZBTB16 expression by accumulating in the ZBTB16 promoter and methylation. FBW7 upregulates the expression of ZBTB16 by targeting histone methyltransferase EZH2 thus reducing the occurrence of T1D.

scholarly journals E3 ubiquitin ligase FBW7-mediated ubiquitination of EZH2 prevents type I diabetes in NOD mice

2020 ◽  
Author(s):  
Jiamei Tian ◽  
Yuanyuan Zhang ◽  
Shanshan Li
Keyword(s):  
Beta Cells ◽  
Inflammatory Cytokines ◽  
Ubiquitin Ligase ◽  
Pancreatic Beta Cells ◽  
Type I Diabetes ◽  
E3 Ubiquitin Ligase ◽  
Nod Mice ◽  
Beta Cell Apoptosis ◽  
Type I ◽  
Pro Inflammatory Cytokines

Abstract Background Type I diabetes (T1D) is a heritable autoimmune disease targeting pancreatic beta cells. This study explores the molecular mechanism of E3 ubiquitin ligase FBW7 in reducing the occurrence of T1D. Methods The protein expression of FBW7, EZH2, and ZBTB16 was quantified in non-obese diabetic (NOD) mouse model of streptozotocin-induced T1D. Next, splenocytes and pancreatic beta cells were isolated to measure production of pro-inflammatory cytokines in splenocytes, as well as islet beta-cell apoptosis. Besides, the stability of EZH2 induced by FBW7 was analyzed by cycloheximide chase assay. The binding affinity of FBW7 and EZH2 and the consequence of ubiquitination were monitored by immunoprecipitation (IP) assay. Last, chromatin immunoprecipitation (ChIP) assay was employed to determine the accumulation of EZH2 and H3K27me3 at the ZBTB16 promoter region. Results We found downregulated FBW7 and ZBTB16, and upregulated EZH2 in diabetic NOD mice. Overexpression of FBW7 in the NOD mice inhibited the production of pro-inflammatory cytokines in the splenocytes and the apoptosis of islets beta cells. FBW7 destabilized EZH2 and accelerated ubiquitin-dependent degradation. EZH2 and H3K27me3 downregulated the ZBTB16 expression by accumulating in the ZBTB16 promoter and methylation. Conclusion FBW7 upregulates the expression of ZBTB16 by targeting histone methyltransferase EZH2 thus reducing the occurrence of T1D.

scholarly journals E3 ubiquitin ligase FBW7-mediated ubiquitination of EZH2 prevents type I diabetes in NOD mice

2020 ◽  
Author(s):  
Jiamei Tian ◽  
Yuanyuan Zhang ◽  
Shanshan Li
Keyword(s):  
Ubiquitin Ligase ◽  
Type I Diabetes ◽  
E3 Ubiquitin Ligase ◽  
Nod Mice ◽  
Type I

Abstract The authors have withdrawn this preprint due to erroneous posting.

Morphological analysis of selective destruction of pancreatic beta-cells by cytotoxic T lymphocytes in NOD mice

Diabetes ◽  
1991 ◽  
Vol 40 (9) ◽  
pp. 1210-1217 ◽  
Author(s):  
M. Hayakawa ◽  
K. Yokono ◽  
M. Nagata ◽  
N. Hatamori ◽  
W. Ogawa ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Beta Cells ◽  
Cytotoxic T Lymphocytes ◽  
Pancreatic Beta Cells ◽  
Morphological Analysis ◽  
Nod Mice ◽  
Selective Destruction

scholarly journals TRIM41 is required to innate antiviral response by polyubiquitinating BCL10 and recruiting NEMO

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Zhou Yu ◽  
Xuelian Li ◽  
Mingjin Yang ◽  
Jiaying Huang ◽  
Qian Fang ◽  
...  
Keyword(s):  
Nucleic Acids ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
B Cell Lymphoma ◽  
Antiviral Response ◽  
Type I Interferons ◽  
Type I ◽  
Innate Response ◽  
Innate Antiviral Response

AbstractSensing of pathogenic nucleic acids by pattern recognition receptors (PRR) not only initiates anti-microbe defense but causes inflammatory and autoimmune diseases. E3 ubiquitin ligase(s) critical in innate response need to be further identified. Here we report that the tripartite motif-containing E3 ubiquitin ligase TRIM41 is required to innate antiviral response through facilitating pathogenic nucleic acids-triggered signaling pathway. TRIM41 deficiency impairs the production of inflammatory cytokines and type I interferons in macrophages after transfection with nucleic acid-mimics and infection with both DNA and RNA viruses. In vivo, TRIM41 deficiency leads to impaired innate response against viruses. Mechanistically, TRIM41 directly interacts with BCL10 (B cell lymphoma 10), a core component of CARD proteins−BCL10 − MALT1 (CBM) complex, and modifies the Lys63-linked polyubiquitylation of BCL10, which, in turn, hubs NEMO for activation of NF-κB and TANK-binding kinase 1 (TBK1) − interferon regulatory factor 3 (IRF3) pathways. Our study suggests that TRIM41 is the potential universal E3 ubiquitin ligase responsible for Lys63 linkage of BCL10 during innate antiviral response, adding new insight into the molecular mechanism for the control of innate antiviral response.

scholarly journals Site-specific ubiquitination exposes a linear motif to promote interferon-α receptor endocytosis

2007 ◽  
Vol 179 (5) ◽  
pp. 935-950 ◽  
Author(s):  
K.G. Suresh Kumar ◽  
Hervé Barriere ◽  
Christopher J. Carbone ◽  
Jianghuai Liu ◽  
Gayathri Swaminathan ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Interferon Α ◽  
Type I ◽  
Lysosomal Degradation ◽  
Linear Motif ◽  
Site Specific ◽  
Receptor Endocytosis ◽  
Β Receptor

Ligand-induced endocytosis and lysosomal degradation of cognate receptors regulate the extent of cell signaling. Along with linear endocytic motifs that recruit the adaptin protein complex 2 (AP2)–clathrin molecules, monoubiquitination of receptors has emerged as a major endocytic signal. By investigating ubiquitin-dependent lysosomal degradation of the interferon (IFN)-α/β receptor 1 (IFNAR1) subunit of the type I IFN receptor, we reveal that IFNAR1 is polyubiquitinated via both Lys48- and Lys63-linked chains. The SCFβTrcp (Skp1–Cullin1–F-box complex) E3 ubiquitin ligase that mediates IFNAR1 ubiquitination and degradation in cells can conjugate both types of chains in vitro. Although either polyubiquitin linkage suffices for postinternalization sorting, both types of chains are necessary but not sufficient for robust IFNAR1 turnover and internalization. These processes also depend on the proximity of ubiquitin-acceptor lysines to a linear endocytic motif and on its integrity. Furthermore, ubiquitination of IFNAR1 promotes its interaction with the AP2 adaptin complex that is required for the robust internalization of IFNAR1, implicating cooperation between site-specific ubiquitination and the linear endocytic motif in regulating this process.

scholarly journals The Matrix Protein of Nipah Virus Targets the E3-Ubiquitin Ligase TRIM6 to Inhibit the IKKε Kinase-Mediated Type-I IFN Antiviral Response

2016 ◽  
Vol 12 (9) ◽  
pp. e1005880 ◽  
Author(s):  
Preeti Bharaj ◽  
Yao E. Wang ◽  
Brian E. Dawes ◽  
Tatyana E. Yun ◽  
Arnold Park ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Matrix Protein ◽  
Nipah Virus ◽  
E3 Ubiquitin Ligase ◽  
Antiviral Response ◽  
Type I ◽  
Type I Ifn ◽  
The Matrix

Interleukin-1 effect on glycemia in the non-obese diabetic mouse at the pre-diabetic stage

1996 ◽  
Vol 148 (1) ◽  
pp. 139-148 ◽  
Author(s):  
A Amrani ◽  
M Jafarian-Tehrani ◽  
P Mormède ◽  
S Durant ◽  
J-M Pleau ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type I Diabetes ◽  
Interleukin 1 ◽  
Nod Mice ◽  
Experimental Models ◽  
Nod Mouse ◽  
Hypoglycemic Effect ◽  
Type I ◽  
Insulin Effect ◽  
Corticosterone Secretion

Abstract Cytokines, particularly interleukin 1 (IL-1) and tumor necrosis factor, are known to induce hypoglycemia in normal rodents or different experimental models of type II diabetes. We investigated, at the pre-diabetic stage, the effect of short-term administration of murine recombinant interleukin-1α (mrIL-1α) on the levels of glucose, insulin and corticosterone in the non-obese diabetic (NOD) mouse, a spontaneous model of type I diabetes. Two-month-old, pre-diabetic NOD mice of both sexes were insensitive to mrIL-1α (12·5 and 50 μg/kg) 2 h after administration, the time at which the maximal decrease (around 50%) was observed in the C57BL/6 mouse strain. Kinetic studies however showed that mrIL-1α lowered glycemia in both sexes of NOD mice, but the effect was limited and delayed. In the NOD and C57BL/6 strains, mrIL-1α had no influence on insulin levels in females, but significantly increased them in males (P<0·0001). Castration of NOD males abrogated the stimulatory effect of mrIL-1α on insulin secretion. Corticosterone secretion was stimulated by mrIL-1α in both sexes of NOD and C57BL/6 mice, and this effect was faster and greater in NOD females than in C57BL/6 females. The incomplete hypoglycemic response to mrIL-1α in females may be attributed to the anti-insulin effect of glucocorticoids, an effect which can be demonstrated when mrIL-1α is administered to adrenalectomized animals or when mrIL-1α is administered together with the glucocorticoid antagonist RU38486. In NOD males, in contrast, glucocorticoids did not play a major role in the limited hypoglycemic response to mrIL-1α, since RU38486 and adrenalectomy were not able to unmask a hypoglycemic effect. Moreover, NOD mice of both sexes were less sensitive than C57BL/6 mice to the hypoglycemic effect of insulin (2·5 U/kg), which suggests some degree of insulin-resistance in NOD mice. With regard to the effect of IL-1 on NOD mouse glycemia, therefore, these results suggest that glucocorticoids and/or androgens, according to the animal's sex, may induce a state of insulin-resistance. Journal of Endocrinology (1996) 148, 139–148

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