scholarly journals Syntaxin 4 Mediates NF-κB Signaling and Chemokine Ligand Expression via Specific Interaction with IκBβ

2021 ◽  
Author(s):  
Ada Admin ◽  
Rajakrishnan Veluthakal ◽  
Eunjin Oh ◽  
Miwon Ahn ◽  
Diti Chatterjee-Bhowmick ◽  
...  
Keyword(s):  
Specific Interaction ◽  
Cell Mass ◽  
Proteasomal Degradation ◽  
Human Islets ◽  
Β Cells ◽  
Chemokine Ligand ◽  
Ligand Expression ◽  
Syntaxin 4 ◽  
Proteosomal Degradation ◽  
Necrosis Factor

Enrichment of human islets with Syntaxin 4 (STX4) improves functional β-cell mass through a nuclear factor- kB (NF-kB)-dependent mechanism. However, the detailed mechanisms underlying the protective effect of STX4 are unknown. To determine the signaling events linking STX4 enrichment and downregulation of NF-kB activity, STX4 was overexpressed in human islets, EndoC-βH1 and INS-1 832/13 cells in culture, and the cells were challenged with the proinflammatory cytokines interleukin-1β, tumor necrosis factor-a and interferon-g, individually and in combination. STX4 expression suppressed cytokine-induced proteasomal degradation of IkBβ but not IkBa. Inhibition of IKKβ prevented IkBβ degradation, suggesting that IKKβ phosphorylates IkBβ. Moreover, the IKKβ inhibitor, as well as a proteosomal degradation inhibitor, prevented the loss of STX4 caused by cytokines. This suggests that STX4 may be phosphorylated by IKKβ in response to cytokines, targeting STX4 for proteosomal degradation. Expression of a stabilized form of STX4 further protected IkBβ from proteasomal degradation, and like wildtype STX4, stabilized STX4 coimmunoprecipitated with IkBβ and the NF-kB p50 subunit. This work proposes a novel pathway wherein STX4 regulates cytokine-induced NF-kB signaling in β-cells <i>via</i> associating with and preventing IkBβ degradation, suppressing chemokine expression, and protecting islet β-cells from cytokine-mediated dysfunction and demise.

scholarly journals Syntaxin 4 Mediates NF-κB Signaling and Chemokine Ligand Expression via Specific Interaction with IκBβ

2021 ◽  
Author(s):  
Ada Admin ◽  
Rajakrishnan Veluthakal ◽  
Eunjin Oh ◽  
Miwon Ahn ◽  
Diti Chatterjee-Bhowmick ◽  
...  
Keyword(s):  
Specific Interaction ◽  
Cell Mass ◽  
Proteasomal Degradation ◽  
Human Islets ◽  
Β Cells ◽  
Chemokine Ligand ◽  
Ligand Expression ◽  
Syntaxin 4 ◽  
Proteosomal Degradation ◽  
Necrosis Factor

Enrichment of human islets with Syntaxin 4 (STX4) improves functional β-cell mass through a nuclear factor- kB (NF-kB)-dependent mechanism. However, the detailed mechanisms underlying the protective effect of STX4 are unknown. To determine the signaling events linking STX4 enrichment and downregulation of NF-kB activity, STX4 was overexpressed in human islets, EndoC-βH1 and INS-1 832/13 cells in culture, and the cells were challenged with the proinflammatory cytokines interleukin-1β, tumor necrosis factor-a and interferon-g, individually and in combination. STX4 expression suppressed cytokine-induced proteasomal degradation of IkBβ but not IkBa. Inhibition of IKKβ prevented IkBβ degradation, suggesting that IKKβ phosphorylates IkBβ. Moreover, the IKKβ inhibitor, as well as a proteosomal degradation inhibitor, prevented the loss of STX4 caused by cytokines. This suggests that STX4 may be phosphorylated by IKKβ in response to cytokines, targeting STX4 for proteosomal degradation. Expression of a stabilized form of STX4 further protected IkBβ from proteasomal degradation, and like wildtype STX4, stabilized STX4 coimmunoprecipitated with IkBβ and the NF-kB p50 subunit. This work proposes a novel pathway wherein STX4 regulates cytokine-induced NF-kB signaling in β-cells <i>via</i> associating with and preventing IkBβ degradation, suppressing chemokine expression, and protecting islet β-cells from cytokine-mediated dysfunction and demise.

scholarly journals Syntaxin 4 Mediates NF-κB Signaling and Chemokine Ligand Expression via Specific Interaction with IκBβ

Diabetes ◽  
2021 ◽  
pp. db200868 ◽  
Author(s):  
Rajakrishnan Veluthakal ◽  
Eunjin Oh ◽  
Miwon Ahn ◽  
Diti Chatterjee-Bhowmick ◽  
Debbie C. Thurmond
Keyword(s):  
Specific Interaction ◽  
Chemokine Ligand ◽  
Ligand Expression ◽  
Syntaxin 4

scholarly journals The Hippo kinase LATS2 impairs pancreatic β-cell survival in diabetes through the mTORC1-autophagy axis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ting Yuan ◽  
Karthika Annamalai ◽  
Shruti Naik ◽  
Blaz Lupse ◽  
Shirin Geravandi ◽  
...  
Keyword(s):  
Cell Survival ◽  
Cell Apoptosis ◽  
Molecular Mechanisms ◽  
Cell Mass ◽  
Human Islets ◽  
Hippo Signaling ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Large Tumor

AbstractDiabetes results from a decline in functional pancreatic β-cells, but the molecular mechanisms underlying the pathological β-cell failure are poorly understood. Here we report that large-tumor suppressor 2 (LATS2), a core component of the Hippo signaling pathway, is activated under diabetic conditions and induces β-cell apoptosis and impaired function. LATS2 deficiency in β-cells and primary isolated human islets as well as β-cell specific LATS2 ablation in mice improves β-cell viability, insulin secretion and β-cell mass and ameliorates diabetes development. LATS2 activates mechanistic target of rapamycin complex 1 (mTORC1), a physiological suppressor of autophagy, in β-cells and genetic and pharmacological inhibition of mTORC1 counteracts the pro-apoptotic action of activated LATS2. We further show a direct interplay between Hippo and autophagy, in which LATS2 is an autophagy substrate. On the other hand, LATS2 regulates β-cell apoptosis triggered by impaired autophagy suggesting an existence of a stress-sensitive multicomponent cellular loop coordinating β-cell compensation and survival. Our data reveal an important role for LATS2 in pancreatic β-cell turnover and suggest LATS2 as a potential therapeutic target to improve pancreatic β-cell survival and function in diabetes.

Insulin signalling in islets

2008 ◽  
Vol 36 (3) ◽  
pp. 290-293 ◽  
Author(s):  
Shanta J. Persaud ◽  
Dany Muller ◽  
Peter M. Jones
Keyword(s):  
Gene Expression ◽  
Insulin Secretion ◽  
Insulin Signalling ◽  
Cell Mass ◽  
Human Islets ◽  
Human Islet ◽  
Mrna Levels ◽  
Small Interfering Rnas ◽  
Β Cells ◽  
Β Cell

Studies in transgenic animals, rodent insulin-secreting cell lines and rodent islets suggest that insulin acts in an autocrine manner to regulate β-cell mass and gene expression. Very little is known about the in vitro roles played by insulin in human islets, and the regulatory role of insulin in protecting against β-cell apoptosis. We have identified mRNAs encoding IRs (insulin receptors) and downstream signalling elements in dissociated human islet β-cells by single-cell RT (reverse transcription)–PCR, and perifusion studies have indicated that insulin does not have an autocrine role to regulate insulin secretion from human islets, but activation of the closely related IGF-1 (insulin-like growth factor 1) receptors is linked to inhibition of insulin secretion. Knockdown of IR mRNA by siRNAs (small interfering RNAs) decreased IR protein expression without affecting IGF-1 receptor levels, and blocked glucose stimulation of preproinsulin gene expression. Similar results were obtained when human islet IRS (IR substrate)-2 was knocked down, whereas depletion of IRS-1 caused an increase in preproinsulin mRNA levels. Studies using the mouse MIN6 β-cell line indicated that glucose protected β-cells from undergoing apoptosis and that this was a consequence, at least in part, of insulin release in response to elevated glucose. IGF-1 also exerted anti-apoptotic effects. These data indicate that insulin can exert autocrine effects in human islets through receptors on β-cells. It protects β-cells against apoptosis and increases preproinsulin mRNA synthesis, but does not affect insulin secretion.

scholarly journals Syntaxin 4 Expression in Pancreatic β-Cells Promotes Islet Function and Protects Functional β-Cell Mass

Diabetes ◽  
2018 ◽  
Vol 67 (12) ◽  
pp. 2626-2639 ◽  
Author(s):  
Eunjin Oh ◽  
Miwon Ahn ◽  
Solomon Afelik ◽  
Thomas C. Becker ◽  
Bart O. Roep ◽  
...  
Keyword(s):  
Cell Mass ◽  
Islet Function ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Syntaxin 4

scholarly journals Syntaxin 4 Eenrichment in β-cells Prevents Conversion to Autoimmune Diabetes in Non-Obese Diabetic (NOD) Mice

2021 ◽  
Author(s):  
Eunjin Oh ◽  
Erika M. McCown ◽  
Miwon Ahn ◽  
Pablo A. Garcia ◽  
Sergio Branciamore ◽  
...  
Keyword(s):  
Autoimmune Diabetes ◽  
Cell Mass ◽  
Nod Mice ◽  
Treg Cells ◽  
Whole Body ◽  
Cell Protection ◽  
Β Cells ◽  
Β Cell ◽  
Syntaxin 4 ◽  
Glucose Responsiveness

Syntaxin 4 (STX4), a plasma membrane-localized SNARE protein, regulates human islet β-cell insulin secretion and preservation of β-cell mass. We found that human type 1 diabetic (T1D) and non-obese diabetic (NOD) mouse islets show reduced β-cell STX4 expression, consistent with decreased STX4 expression as a potential driver of T1D phenotypes. To test this hypothesis, we generated inducible β-cell-specific STX4-expressing NOD mice (NOD-iβSTX4).<b> </b>Of NOD-iβSTX4 mice, 73% had sustained normoglycemia versus <20% of control NOD (NOD-Ctrl) mice, by 25 weeks of age. At 12 weeks of age, prior to diabetes conversion, NOD-iβSTX4 mice demonstrated superior whole-body glucose tolerance and β-cell glucose responsiveness than NOD-Ctrl mice. Higher β-cell mass and reduced β-cell apoptosis were also detected in NOD-iβSTX4 pancreata compared with those of NOD-Ctrl mice. Single-cell RNA‐sequencing revealed that islets from NOD-iβSTX4 had markedly reduced IFNƔ signaling and TNFα signaling via NF-ĸB in islet β-cells, including reduced expression of the chemokine CCL5; CD4<sup>+</sup> Treg cells were also enriched in NOD-iβSTX4 islets. These results provide a deeper mechanistic understanding of STX4 function in β-cell protection and warrant further investigation of STX4 enrichment as a strategy to reverse or prevent T1D in humans or protect β-cell grafts.

scholarly journals Neratinib protects pancreatic beta cells in diabetes

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Amin Ardestani ◽  
Sijia Li ◽  
Karthika Annamalai ◽  
Blaz Lupse ◽  
Shirin Geravandi ◽  
...  
Keyword(s):  
Pancreatic Beta Cells ◽  
Cell Function ◽  
Cell Mass ◽  
Human Islets ◽  
Β Cells ◽  
Β Cell

Abstract The loss of functional insulin-producing β-cells is a hallmark of diabetes. Mammalian sterile 20-like kinase 1 (MST1) is a key regulator of pancreatic β-cell death and dysfunction; its deficiency restores functional β-cells and normoglycemia. The identification of MST1 inhibitors represents a promising approach for a β-cell-protective diabetes therapy. Here, we identify neratinib, an FDA-approved drug targeting HER2/EGFR dual kinases, as a potent MST1 inhibitor, which improves β-cell survival under multiple diabetogenic conditions in human islets and INS-1E cells. In a pre-clinical study, neratinib attenuates hyperglycemia and improves β-cell function, survival and β-cell mass in type 1 (streptozotocin) and type 2 (obese Leprdb/db) diabetic mouse models. In summary, neratinib is a previously unrecognized inhibitor of MST1 and represents a potential β-cell-protective drug with proof-of-concept in vitro in human islets and in vivo in rodent models of both type 1 and type 2 diabetes.

scholarly journals Decrease in Ins+Glut2LO β-cells with advancing age in mouse and human pancreas

2017 ◽  
Vol 233 (3) ◽  
pp. 229-241 ◽  
Author(s):  
Christine A Beamish ◽  
Sofia Mehta ◽  
Brenda J Strutt ◽  
Subrata Chakrabarti ◽  
Manami Hara ◽  
...  
Keyword(s):  
Glucose Transporter ◽  
Cell Mass ◽  
Positive Association ◽  
Human Islets ◽  
Human Pancreas ◽  
Fetal Life ◽  
Β Cells ◽  
Β Cell ◽  
Cell Clusters ◽  
Glucose Transporter 2

The presence and location of resident pancreatic β-cell progenitors is controversial. A subpopulation of insulin-expressing but glucose transporter-2-low (Ins+Glut2LO) cells may represent multipotent pancreatic progenitors in adult mouse and in human islets, and they are enriched in small, extra-islet β-cell clusters (<5 β cells) in mice. Here, we sought to identify and compare the ontogeny of these cells in mouse and human pancreata throughout life. Mouse pancreata were collected at postnatal days 7, 14, 21, 28, and at 3, 6, 12, and 18 months of age, and in the first 28 days after β-cell mass depletion following streptozotocin (STZ) administration. Samples of human pancreas were examined during fetal life (22–30 weeks gestation), infancy (0–1 year), childhood (2–9), adolescence (10–17), and adulthood (18–80). Tissues were analyzed by immunohistochemistry for the expression and location of insulin, GLUT2 and Ki67. The proportion of β cells within clusters relative to that in islets was higher in pancreas of human than of mouse at all ages examined, and decreased significantly at adolescence. In mice, the total number of Ins+Glut2LO cells decreased after 7 days concurrent with the proportion of clusters. These cells were more abundant in clusters than in islets in both species. A positive association existed between the appearance of new β cells after the STZ treatment of young mice, particularly in clusters and smaller islets, and an increased proportional presence of Ins+Glut2LO cells during early β-cell regeneration. These data suggest that Ins+Glut2LO cells are preferentially located within β-cell clusters throughout life in pancreas of mouse and human, and may represent a source of β-cell plasticity.

scholarly journals Bromodomain protein inhibition protects β-cells from cytokine-induced death and dysfunction via antagonism of NF-κB pathway

2020 ◽  
Author(s):  
Vinny Negi ◽  
Jeongkyung Lee ◽  
Ruya Liu ◽  
Eliana M. Perez-Garcia ◽  
Feng Li ◽  
...  
Keyword(s):  
Cell Apoptosis ◽  
Cell Function ◽  
Cell Mass ◽  
Human Islets ◽  
Β Cells ◽  
Β Cell ◽  
Bet Inhibitors ◽  
Β Cell Function ◽  
Underlying Mechanisms

ABSTRACTCytokine induced β-cell apoptosis is the major pathogenic mechanism in type 1 diabetes (T1D). Despite significant advances in understanding underlying mechanisms, few drugs have been translated to protect β-cells in T1D. Epigenetic modulators such as bromodomain-containing BET (Bromo- and Extra-Terminal) proteins are important regulators of immune responses. Pre-clinical studies have demonstrated a protective effect of BET inhibitors in NOD (non-obese diabetes) mouse model of T1D. However, the role of BET proteins in β-cell function in response to cytokines is unknown. Here we demonstrate that I-BET, a BET protein inhibitor, protected β-cells from cytokine induced dysfunction and death. In vivo administration of I-BET to mice exposed to low-dose STZ (streptozotocin), a model of T1D, significantly reduced β-cell apoptosis and preserved β-cell mass, suggesting a cytoprotective function of I-BET. Furthermore, human islets treated with I-BET displayed better glucose stimulated insulin secretion compared to controls, when exposed to cytokines. Mechanistically, RNA-Seq analysis revealed I-BET treatment suppressed pathways involved in apoptosis, including NF-kB signaling, while maintaining the expression of genes critical for β-cell function, such as Pdx1 and Ins1. Taken together, this study demonstrates that I-BET is effective in protecting β-cells from cytokine-induced dysfunction and apoptosis, and may have potential therapeutic values in T1D.

scholarly journals Syntaxin 4 Eenrichment in β-cells Prevents Conversion to Autoimmune Diabetes in Non-Obese Diabetic (NOD) Mice

2021 ◽  
Author(s):  
Eunjin Oh ◽  
Erika M. McCown ◽  
Miwon Ahn ◽  
Pablo A. Garcia ◽  
Sergio Branciamore ◽  
...  
Keyword(s):  
Autoimmune Diabetes ◽  
Cell Mass ◽  
Nod Mice ◽  
Treg Cells ◽  
Whole Body ◽  
Cell Protection ◽  
Β Cells ◽  
Β Cell ◽  
Syntaxin 4 ◽  
Glucose Responsiveness

Syntaxin 4 (STX4), a plasma membrane-localized SNARE protein, regulates human islet β-cell insulin secretion and preservation of β-cell mass. We found that human type 1 diabetic (T1D) and non-obese diabetic (NOD) mouse islets show reduced β-cell STX4 expression, consistent with decreased STX4 expression as a potential driver of T1D phenotypes. To test this hypothesis, we generated inducible β-cell-specific STX4-expressing NOD mice (NOD-iβSTX4).<b> </b>Of NOD-iβSTX4 mice, 73% had sustained normoglycemia versus <20% of control NOD (NOD-Ctrl) mice, by 25 weeks of age. At 12 weeks of age, prior to diabetes conversion, NOD-iβSTX4 mice demonstrated superior whole-body glucose tolerance and β-cell glucose responsiveness than NOD-Ctrl mice. Higher β-cell mass and reduced β-cell apoptosis were also detected in NOD-iβSTX4 pancreata compared with those of NOD-Ctrl mice. Single-cell RNA‐sequencing revealed that islets from NOD-iβSTX4 had markedly reduced IFNƔ signaling and TNFα signaling via NF-ĸB in islet β-cells, including reduced expression of the chemokine CCL5; CD4<sup>+</sup> Treg cells were also enriched in NOD-iβSTX4 islets. These results provide a deeper mechanistic understanding of STX4 function in β-cell protection and warrant further investigation of STX4 enrichment as a strategy to reverse or prevent T1D in humans or protect β-cell grafts.

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