Pancreatic β-cell protection from inflammatory stress by the endoplasmic reticulum proteins thrombospondin 1 and mesencephalic astrocyte-derived neutrotrophic factor (MANF)

Cunha, Daniel Andrade Da; Cito, Monia; Grieco, Fabio Arturo; Cristina, Carolina; Danilova, Tatiana; Ladrière, Laurence; Lindahl, Maria; Domanskyi, Andrii; Bugliani, Marco; Marchetti, Piero; Eizirik, Décio L.; Cnop, Miriam

doi:10.1074/jbc.m116.769877

Cited by 42 publications

(43 citation statements)

References 54 publications

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“…In this study, we demonstrated that the MANF protein intensifies islet b-cell proliferation from aged mice, suggesting that MANF could partly reverse age-dependent repression of b-cell replication. Previously, we found that recombinant MANF protein partially rescues mouse and human b-cells from cytokine-and ER stress-induced cell death in culture (30,38) and induces human b-cell proliferation (30). Here, we show that Manf mRNA is upregulated in mouse b-cells in hyperglycemic conditions in vitro and that MANF protein reduces ER stress-induced glucotoxicity in mouse b-cells.…”

Section: Discussionmentioning

confidence: 51%

“…We show that MANF resides in the ER where it modulates ER stress and is crucial for b-cell survival. Upon ER stress, MANF is secreted from b-cells (30), and rhMANF has protective and restorative effects when applied exogenously to human and mouse b-cells (30,38). Thus, MANF seems to have a dual mode of action: 1) cotranslationally where it inserts in the ER, thereby modulating ER stress, and 2) extracellularly (possibly through autocrine/paracrine signaling) by activating a signal transduction pathway and/or being endocytosed and transported to the ER.…”

Section: Discussionmentioning

confidence: 99%

“…We previously demonstrated that MANF partially protects mouse b-cells from thapsigargin-induced cell death in vitro (38). Herein, we analyzed whether MANF protects isolated mouse islet b-cells from glucotoxicity.…”

Section: Effects Of Recombinant Manf Protein In Vitromentioning

confidence: 98%

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MANF Is Required for the Postnatal Expansion and Maintenance of Pancreatic β-Cell Mass in Mice

Danilova

Belevich

et al. 2018

Diabetes

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Global lack of mesencephalic astrocyte-derived neurotropic factor (MANF) leads to progressive postnatal loss of b-cell mass and insulin-dependent diabetes in mice. Similar to Manf 2/2 mice, embryonic ablation of MANF specifically from the pancreas results in diabetes. In this study, we assessed the importance of MANF for the postnatal expansion of pancreatic b-cell mass and for adult b-cell maintenance in mice. Detailed analysis of Pdx-1Cre +/2 ::Manf fl/fl mice revealed mosaic MANF expression in postnatal pancreata and a significant correlation between the number of MANF-positive b-cells and b-cell mass in individual mice. In vitro, recombinant MANF induced b-cell proliferation in islets from aged mice and protected from hyperglycemia-induced endoplasmic reticulum (ER) stress. Consequently, excision of MANF from b-cells of adult MIP-1Cre ERT ::Manf fl/fl mice resulted in reduced b-cell mass and diabetes caused largely by b-cell ER stress and apoptosis, possibly accompanied by b-cell dedifferentiation and reduced rates of b-cell proliferation. Thus, MANF expression in adult mouse b-cells is needed for their maintenance in vivo. We also revealed a mechanistic link between ER stress and inflammatory signaling pathways leading to b-cell death in the absence of MANF. Hence, MANF might be a potential target for regenerative therapy in diabetes.

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Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 99%

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MANF Is Required for the Postnatal Expansion and Maintenance of Pancreatic β-Cell Mass in Mice

Danilova

Belevich

et al. 2018

Diabetes

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“…153 It is interesting that this cell-protective effect was only induced by intracellular TSP1 engineered with an ER retention KDEL sequence and was not observed with conditioned medium TSP1. 153,154 In this pancreatic βcell system, ER TSP1 colocalized with protein disulfide isomerase. Further studies showed that TSP1 was also cytoprotective to β cells acutely exposed to the inflammatory cytokines interleukin-1β or interferon-γ or to thapsigargin-induced ER stress, although prolonged exposure (4-24 hr) resulted in downregulation of TSP1 expression and proteosomal degradation, leading to cell death.…”

Section: Intracellular Tsp1 As An Er Stress Regulator Of Ecmmentioning

confidence: 96%

Thrombospondin 1 and Its Diverse Roles as a Regulator of Extracellular Matrix in Fibrotic Disease

Murphy-Ullrich

2019

J Histochem Cytochem.

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Thrombospondin 1 (TSP1) is a matricellular extracellular matrix protein that has diverse roles in regulating cellular processes important for the pathogenesis of fibrotic diseases. We will present evidence for the importance of TSP1 control of latent transforming growth factor beta activation in renal fibrosis with an emphasis on diabetic nephropathy. Other functions of TSP1 that affect renal fibrosis, including regulation of inflammation and capillary density, will be addressed. Emerging roles for TSP1 N-terminal domain regulation of collagen matrix assembly, direct effects of TSP1-collagen binding, and intracellular functions of TSP1 in mediating endoplasmic reticulum stress responses in extracellular matrix remodeling and fibrosis, which could potentially affect renal fibrogenesis, will also be discussed. Finally, we will address possible strategies for targeting TSP1 functions to treat fibrotic renal disease. (J Histochem Cytochem 67: 683-699, 2019)

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“…Knockout of THBS1 results in mitochondrial dysfunction in mice (21). THBS1 can prevent mitochondrial pathway of apoptosis from being triggered (35) and inhibits palmitate-induced release of mitochondrial cytochrome c, cleavage of capase-3, and apoptosis (36), indicat-…”

Section: Discussionmentioning

confidence: 99%

microRNA-222 Attenuates Mitochondrial Dysfunction During Transmissible Gastroenteritis Virus Infection

Zhao

Song

Bai

et al. 2019

Molecular & Cellular Proteomics

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In BriefZhao et al. identify microRNA-222 as a mediator of mitochondrial dysfunction, THBS1, and CD47 induced during TGEV infection and showed that mi-croRNA-222 inhibits TGEV-induced mitochondrial dysfunction via targeting and downregulating CD47. Graphical Abstract Highlights• microRNA-222 attenuates TGEV-induced mitochondrial dysfunction.• microRNA-222 downregulates THBS1 and CD47.• THBS1 is the target of microRNA-222 during TGEV infection.• THBS1 and CD47 increase mitochondrial Ca 2ϩ level and reduced mitochondrial membrane potential (MMP). Transmissible gastroenteritis virus (TGEV) is a member of Coronaviridae family. Our previous research showed that TGEV infection could induce mitochondrial dysfunction and upregulate miR-222 level. Therefore, we presumed that miR-222 might be implicated in regulating mitochondrial dysfunction induced by TGEV infection. To verify the hypothesis, the effect of miR-222 on mitochondrial dysfunction was tested and we showed that miR-222 attenuated TGEV-induced mitochondrial dysfunction. To investigate the underlying molecular mechanism of miR-222 in TGEV-induced mitochondrial dysfunction, a quantitative proteomic analysis of PK-15 cells that were transfected with miR-222 mimics and infected with TGEV was per-formed. In total, 4151 proteins were quantified and 100 differentially expressed proteins were obtained (57 upregulated, 43 downregulated), among which thrombospondin-1 (THBS1) and cluster of differentiation 47 (CD47) were downregulated. THBS1 was identified as the target of miR-222. Knockdown of THBS1 and CD47 decreased mitochondrial Ca 2؉ level and increased mitochondrial membrane potential (MMP) level. Reversely, overexpression of THBS1 and CD47 elevated mitochondrial Ca 2؉ level and reduced mitochondrial membrane potential (MMP) level. Together, our data establish a significant role of miR-222 in regulating mitochondrial dysfunction in response to TGEV infection.

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Pancreatic β-cell protection from inflammatory stress by the endoplasmic reticulum proteins thrombospondin 1 and mesencephalic astrocyte-derived neutrotrophic factor (MANF)

Cited by 42 publications

References 54 publications

MANF Is Required for the Postnatal Expansion and Maintenance of Pancreatic β-Cell Mass in Mice

MANF Is Required for the Postnatal Expansion and Maintenance of Pancreatic β-Cell Mass in Mice

Thrombospondin 1 and Its Diverse Roles as a Regulator of Extracellular Matrix in Fibrotic Disease

microRNA-222 Attenuates Mitochondrial Dysfunction During Transmissible Gastroenteritis Virus Infection

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