O-GlcNacylation Links TxNIP to Inflammasome Activation in Pancreatic β Cells
Thioredoxin interacting protein (TxNIP), which strongly responds to glucose, has emerged as a central mediator of glucotoxicity in pancreatic β cells. TxNIP is a scaffold protein interacting with target proteins to inhibit or stimulate their activity. Recent studies reported that high glucose stimul...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-05-01
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| Series: | Frontiers in Endocrinology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fendo.2019.00291/full |
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DOAJ |
| language |
English |
| format |
Article |
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DOAJ |
| author |
Gaelle Filhoulaud Gaelle Filhoulaud Gaelle Filhoulaud Fadila Benhamed Fadila Benhamed Fadila Benhamed Patrick Pagesy Patrick Pagesy Patrick Pagesy Caroline Bonner Caroline Bonner Yann Fardini Yann Fardini Yann Fardini Anissa Ilias Anissa Ilias Jamileh Movassat Jamileh Movassat Anne-Françoise Burnol Anne-Françoise Burnol Anne-Françoise Burnol Sandra Guilmeau Sandra Guilmeau Sandra Guilmeau Julie Kerr-Conte François Pattou François Pattou Tarik Issad Tarik Issad Tarik Issad Catherine Postic Catherine Postic Catherine Postic |
| spellingShingle |
Gaelle Filhoulaud Gaelle Filhoulaud Gaelle Filhoulaud Fadila Benhamed Fadila Benhamed Fadila Benhamed Patrick Pagesy Patrick Pagesy Patrick Pagesy Caroline Bonner Caroline Bonner Yann Fardini Yann Fardini Yann Fardini Anissa Ilias Anissa Ilias Jamileh Movassat Jamileh Movassat Anne-Françoise Burnol Anne-Françoise Burnol Anne-Françoise Burnol Sandra Guilmeau Sandra Guilmeau Sandra Guilmeau Julie Kerr-Conte François Pattou François Pattou Tarik Issad Tarik Issad Tarik Issad Catherine Postic Catherine Postic Catherine Postic O-GlcNacylation Links TxNIP to Inflammasome Activation in Pancreatic β Cells Frontiers in Endocrinology O-GlcNAcylation TXNIP (thioredoxin-interacting protein) pancreatic beta cells hyperglycemia inflammasome |
| author_facet |
Gaelle Filhoulaud Gaelle Filhoulaud Gaelle Filhoulaud Fadila Benhamed Fadila Benhamed Fadila Benhamed Patrick Pagesy Patrick Pagesy Patrick Pagesy Caroline Bonner Caroline Bonner Yann Fardini Yann Fardini Yann Fardini Anissa Ilias Anissa Ilias Jamileh Movassat Jamileh Movassat Anne-Françoise Burnol Anne-Françoise Burnol Anne-Françoise Burnol Sandra Guilmeau Sandra Guilmeau Sandra Guilmeau Julie Kerr-Conte François Pattou François Pattou Tarik Issad Tarik Issad Tarik Issad Catherine Postic Catherine Postic Catherine Postic |
| author_sort |
Gaelle Filhoulaud |
| title |
O-GlcNacylation Links TxNIP to Inflammasome Activation in Pancreatic β Cells |
| title_short |
O-GlcNacylation Links TxNIP to Inflammasome Activation in Pancreatic β Cells |
| title_full |
O-GlcNacylation Links TxNIP to Inflammasome Activation in Pancreatic β Cells |
| title_fullStr |
O-GlcNacylation Links TxNIP to Inflammasome Activation in Pancreatic β Cells |
| title_full_unstemmed |
O-GlcNacylation Links TxNIP to Inflammasome Activation in Pancreatic β Cells |
| title_sort |
o-glcnacylation links txnip to inflammasome activation in pancreatic β cells |
| publisher |
Frontiers Media S.A. |
| series |
Frontiers in Endocrinology |
| issn |
1664-2392 |
| publishDate |
2019-05-01 |
| description |
Thioredoxin interacting protein (TxNIP), which strongly responds to glucose, has emerged as a central mediator of glucotoxicity in pancreatic β cells. TxNIP is a scaffold protein interacting with target proteins to inhibit or stimulate their activity. Recent studies reported that high glucose stimulates the interaction of TxNIP with the inflammasome protein NLRP3 (NLR family, pyrin domain containing 3) to increase interleukin-1 β (IL1β) secretion by pancreatic β cells. To better understand the regulation of TxNIP by glucose in pancreatic β cells, we investigated the implication of O-linked β-N-acetylglucosamine (O-GlcNAcylation) in regulating TxNIP at the posttranslational level. O-GlcNAcylation of proteins is controlled by two enzymes: the O-GlcNAc transferase (OGT), which transfers a monosaccharide to serine/threonine residues on target proteins, and the O-GlcNAcase (OGA), which removes it. Our study shows that TxNIP is subjected to O-GlcNAcylation in response to high glucose concentrations in β cell lines. Modification of the O-GlcNAcylation pathway through manipulation of OGT or OGA expression or activity significantly modulates TxNIP O-GlcNAcylation in INS1 832/13 cells. Interestingly, expression and O-GlcNAcylation of TxNIP appeared to be increased in islets of diabetic rodents. At the mechanistic level, the induction of the O-GlcNAcylation pathway in human and rat islets promotes inflammasome activation as evidenced by enhanced cleaved IL1β. Overexpression of OGT in HEK293 or INS1 832/13 cells stimulates TxNIP and NLRP3 interaction, while reducing TxNIP O-GlcNAcylation through OGA overexpression destabilizes this interaction. Altogether, our study reveals that O-GlcNAcylation represents an important regulatory mechanism for TxNIP activity in β cells. |
| topic |
O-GlcNAcylation TXNIP (thioredoxin-interacting protein) pancreatic beta cells hyperglycemia inflammasome |
| url |
https://www.frontiersin.org/article/10.3389/fendo.2019.00291/full |
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doaj-9c5a66758ef54b9384f0c41f8fdc18bd2020-11-25T00:53:57ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922019-05-011010.3389/fendo.2019.00291451383O-GlcNacylation Links TxNIP to Inflammasome Activation in Pancreatic β CellsGaelle Filhoulaud0Gaelle Filhoulaud1Gaelle Filhoulaud2Fadila Benhamed3Fadila Benhamed4Fadila Benhamed5Patrick Pagesy6Patrick Pagesy7Patrick Pagesy8Caroline Bonner9Caroline Bonner10Yann Fardini11Yann Fardini12Yann Fardini13Anissa Ilias14Anissa Ilias15Jamileh Movassat16Jamileh Movassat17Anne-Françoise Burnol18Anne-Françoise Burnol19Anne-Françoise Burnol20Sandra Guilmeau21Sandra Guilmeau22Sandra Guilmeau23Julie Kerr-Conte24François Pattou25François Pattou26Tarik Issad27Tarik Issad28Tarik Issad29Catherine Postic30Catherine Postic31Catherine Postic32INSERM U1016, Institut Cochin, Paris, FranceCNRS UMR 8104, Paris, FranceUniversité Paris Descartes, Sorbonne Paris Cité, Paris, FranceINSERM U1016, Institut Cochin, Paris, FranceCNRS UMR 8104, Paris, FranceUniversité Paris Descartes, Sorbonne Paris Cité, Paris, FranceINSERM U1016, Institut Cochin, Paris, FranceCNRS UMR 8104, Paris, FranceUniversité Paris Descartes, Sorbonne Paris Cité, Paris, FrancePasteur Institute de Lille, Lille, FranceINSERM U1190 - EGID, Lille, FranceINSERM U1016, Institut Cochin, Paris, FranceCNRS UMR 8104, Paris, FranceUniversité Paris Descartes, Sorbonne Paris Cité, Paris, FranceUMR8251-CNRS, Paris, FranceUniversité Paris Diderot, Sorbonne Paris Cité, Paris, FranceUMR8251-CNRS, Paris, FranceUniversité Paris Diderot, Sorbonne Paris Cité, Paris, FranceINSERM U1016, Institut Cochin, Paris, FranceCNRS UMR 8104, Paris, FranceUniversité Paris Descartes, Sorbonne Paris Cité, Paris, FranceINSERM U1016, Institut Cochin, Paris, FranceCNRS UMR 8104, Paris, FranceUniversité Paris Descartes, Sorbonne Paris Cité, Paris, FranceINSERM U1190 - EGID, Lille, FranceINSERM U1190 - EGID, Lille, FranceCHU, Lille, FranceINSERM U1016, Institut Cochin, Paris, FranceCNRS UMR 8104, Paris, FranceUniversité Paris Descartes, Sorbonne Paris Cité, Paris, FranceINSERM U1016, Institut Cochin, Paris, FranceCNRS UMR 8104, Paris, FranceUniversité Paris Descartes, Sorbonne Paris Cité, Paris, FranceThioredoxin interacting protein (TxNIP), which strongly responds to glucose, has emerged as a central mediator of glucotoxicity in pancreatic β cells. TxNIP is a scaffold protein interacting with target proteins to inhibit or stimulate their activity. Recent studies reported that high glucose stimulates the interaction of TxNIP with the inflammasome protein NLRP3 (NLR family, pyrin domain containing 3) to increase interleukin-1 β (IL1β) secretion by pancreatic β cells. To better understand the regulation of TxNIP by glucose in pancreatic β cells, we investigated the implication of O-linked β-N-acetylglucosamine (O-GlcNAcylation) in regulating TxNIP at the posttranslational level. O-GlcNAcylation of proteins is controlled by two enzymes: the O-GlcNAc transferase (OGT), which transfers a monosaccharide to serine/threonine residues on target proteins, and the O-GlcNAcase (OGA), which removes it. Our study shows that TxNIP is subjected to O-GlcNAcylation in response to high glucose concentrations in β cell lines. Modification of the O-GlcNAcylation pathway through manipulation of OGT or OGA expression or activity significantly modulates TxNIP O-GlcNAcylation in INS1 832/13 cells. Interestingly, expression and O-GlcNAcylation of TxNIP appeared to be increased in islets of diabetic rodents. At the mechanistic level, the induction of the O-GlcNAcylation pathway in human and rat islets promotes inflammasome activation as evidenced by enhanced cleaved IL1β. Overexpression of OGT in HEK293 or INS1 832/13 cells stimulates TxNIP and NLRP3 interaction, while reducing TxNIP O-GlcNAcylation through OGA overexpression destabilizes this interaction. Altogether, our study reveals that O-GlcNAcylation represents an important regulatory mechanism for TxNIP activity in β cells.https://www.frontiersin.org/article/10.3389/fendo.2019.00291/fullO-GlcNAcylationTXNIP (thioredoxin-interacting protein)pancreatic beta cellshyperglycemiainflammasome |