The type 1 diabetes gene TYK2 regulates β-cell development and its responses to interferon-α

Chandra, Vikash; Ibrahim, Hazem; Halliez, Clémentine; Prasad, Rashmi B.; Vecchio, Federica; Dwivedi, Om Prakash; Kvist, Jouni; Balboa, Diego; Saarimäki-Vire, Jonna; Montaser, Hossam; Barsby, Tom; Lithovius, Väinö; Artner, Isabella; Gopalakrishnan, Swetha; Groop, Leif; Mallone, Roberto; Eizirik, Décio L.; Otonkoski, Timo

doi:10.1038/s41467-022-34069-z

Cited by 33 publications

(46 citation statements)

References 57 publications

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“…MDA5) encode viral dsRNA cytoplasmic receptors 6 . The interaction between genetic variants in T1D candidate genes and viral infections have been studied these past years, demonstrating that T1D risk alleles hyperactivate antiviral and pro-inflammatory responses in pancreatic β cells, that eventually lead to β cell destruction and T1D development [45][46][47][48] .…”

Section: Discussionmentioning

confidence: 99%

“…Many of the T1D candidate genes characterized so far have been implicated in the regulation of antiviral and pro-inflammatory responses at the pancreatic β cell level 44 . Some participate in the regulation of the type I IFN signaling, such as PTPN2 and TYK2 , by regulating the type I IFN-induced JAK/STAT signaling pathway 3,4,45 , while others (e.g. MDA5 ) encode viral dsRNA cytoplasmic receptors 6 .…”

Section: Discussionmentioning

confidence: 99%

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The type 1 diabetes-associated lncRNAARGIparticipates in virus-induced pancreatic β cell inflammation

González-Moro

Garcia-Etxebarria

Mendoza

et al. 2022

Preprint

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Type 1 diabetes-associated single nucleotide polymorphisms are mainly located in non-coding regions of the human genome. Single nucleotide polymorphisms located in long non-coding RNAs may result in the disruption of their secondary structure, affecting their function. Here, we functionally characterized the virus-induced type 1 diabetes-associated lncRNA ARGI (Antiviral Response Gene Inducer). ARGI upregulation in pancreatic beta cells leads to the transcriptional activation of antiviral and pro-inflammatory genes. Upon a viral insult, ARGI is upregulated in the nuclei of pancreatic beta cells and binds to CTCF to interact with the regulatory regions of IFNbeta and interferon-stimulated genes, promoting their transcriptional activation in an allele-specific manner. The presence of the risk allele for type 1 diabetes in ARGI induces an hyperactivation of type I IFN response in beta cells, an expression signature that is present in the pancreas of diabetic patients. These data shed light on the molecular mechanisms by which type 1 diabetes-related single nucleotide polymorphisms in long non-coding RNAs influence pathogenesis at the pancreatic beta cell level.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The type 1 diabetes-associated lncRNAARGIparticipates in virus-induced pancreatic β cell inflammation

González-Moro

Garcia-Etxebarria

Mendoza

et al. 2022

Preprint

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“…TYK2 is crucial for cell development and IFNα-mediated responses in human beta cells [11,21,22]. Partial TYK2 knockdown protected human beta cells against apoptosis and inflammation induced by polyinosinic-polycitidilic acid (poly(I:C)), a mimic of double-stranded RNA produced during viral infection [21].…”

Section: Introductionmentioning

confidence: 99%

“…Lately, attention has been focused on TYK2 , a candidate gene for type 1 diabetes whose genetic variants that decrease TYK2 activity are associated with protection against the disease [18–20]. TYK2 is crucial for cell development and IFNα-mediated responses in human beta cells [11, 21, 22]. Partial TYK2 knockdown protected human beta cells against apoptosis and inflammation induced by polyinosinic-polycitidilic acid (poly(I:C)), a mimic of double-stranded RNA produced during viral infection [21].…”

Section: Introductionmentioning

confidence: 99%

“…The copyright holder for this preprint this version posted December 29, 2022. ; https://doi.org/10.1101/2022.12.27.522037 doi: bioRxiv preprint inhibition decreased T-cell-mediated cytotoxicity by preventing IFNα-induced antigen processing and presentation, including MHC class Ι expression [22]. As these findings place TYK2 as a critical regulator of the type I IFN signalling pathway in beta cells, selective TYK2 inhibition has emerged as a drug target to treat type 1 diabetes.…”

Section: Introductionmentioning

confidence: 99%

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Deucravacitinib, a tyrosine kinase 2 pseudokinase inhibitor, protects human beta cells against proinflammatory insults

Santos

Guzman-Llorens

Perez-Serna

et al. 2022

Preprint

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Aims/hypothesis: Type 1 diabetes is characterised by pancreatic islet inflammation and autoimmune-driven pancreatic beta cell destruction. Type I interferons, such as IFNalpha, are key players in early human type 1 diabetes pathogenesis, as the activation of the tyrosine kinase 2 (TYK2)-signal transducer and activator of transcription (STAT) pathway induces inflammation, a long-lasting MHC class I overexpression, endoplasmic reticulum (ER) stress, and beta cell apoptosis (in synergy with IL-beta). As TYK2 inhibition has been suggested as a potential therapeutic target for the prevention or treatment of type 1 diabetes, we investigated whether the selective TYK2 inhibitor deucravacitinib could protect beta cells against the damaging effects of IFNalpha and other proinflammatory cytokines (i.e. IFNgamma and IL-1beta). Methods: Inflammation, ER stress, and apoptosis were evaluated by real-time PCR, immunoblot, immunofluorescence, and nuclear dyes. The promoter activity was assessed by luciferase assay and insulin secretion and content by ELISA. All experiments were performed in the human EndoC-betaH1 cell line. Results: Pre-treatment with deucravacitinib prevented IFNalpha effects, such as STAT1 and STAT2 phosphorylation and protein expression as well as MHC class I hyperexpression, in a dose-dependent manner without affecting beta cell survival and function. Comparison between deucravacitinib and two Janus kinase inhibitors, ruxolitinib and baricitinib, showed that deucravacitinib blocked IFNalpha- but not IFNgamma-induced signalling pathway. Pre-treatment with deucravacitinib protected beta cells from the pro-apoptotic and proinflammatory effects of two different combinations of cytokines: IFNalpha + IL-beta and IFNgamma + IL-1beta. Moreover, this TYK2 inhibitor could partially revert apoptosis and inflammation in cells previously treated with IFNalpha + IL-1beta or IFNgamma + IL-beta. Conclusions/interpretation: Our findings suggest that, by protecting beta cells against the deleterious effects of proinflammatory cytokines without affecting beta cell function and survival, deucravacitinib could be repurposed for the prevention or treatment of early type 1 diabetes.

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LncRNA ARGI Contributes to Virus‐Induced Pancreatic β Cell Inflammation Through Transcriptional Activation of IFN‐Stimulated Genes

et al. 2023

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Type 1 diabetes (T1D) is a complex autoimmune disease that develops in genetically susceptible individuals. Most T1D‐associated single nucleotide polymorphisms (SNPs) are located in non‐coding regions of the human genome. Interestingly, SNPs in long non‐coding RNAs (lncRNAs) may result in the disruption of their secondary structure, affecting their function, and in turn, the expression of potentially pathogenic pathways. In the present work, the function of a virus‐induced T1D‐associated lncRNA named ARGI (Antiviral Response Gene Inducer) is characterized. Upon a viral insult, ARGI is upregulated in the nuclei of pancreatic β cells and binds to CTCF to interact with the promoter and enhancer regions of IFNβ and interferon‐stimulated genes, promoting their transcriptional activation in an allele‐specific manner. The presence of the T1D risk allele in ARGI induces a change in its secondary structure. Interestingly, the T1D risk genotype induces hyperactivation of type I IFN response in pancreatic β cells, an expression signature that is present in the pancreas of T1D patients. These data shed light on the molecular mechanisms by which T1D‐related SNPs in lncRNAs influence pathogenesis at the pancreatic β cell level and opens the door for the development of therapeutic strategies based on lncRNA modulation to delay or avoid pancreatic β cell inflammation in T1D.

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The type 1 diabetes gene TYK2 regulates β-cell development and its responses to interferon-α

Cited by 33 publications

References 57 publications

The type 1 diabetes-associated lncRNAARGIparticipates in virus-induced pancreatic β cell inflammation

The type 1 diabetes-associated lncRNAARGIparticipates in virus-induced pancreatic β cell inflammation

Deucravacitinib, a tyrosine kinase 2 pseudokinase inhibitor, protects human beta cells against proinflammatory insults

LncRNA ARGI Contributes to Virus‐Induced Pancreatic β Cell Inflammation Through Transcriptional Activation of IFN‐Stimulated Genes

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