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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Jun 05, 2024 |
| Title |
Inhibition of the Eukaryotic Initiation Factor-2-α Kinase PERK Decreases Risk of Autoimmune Diabetes in Mice |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Prevention or delay of autoimmune type 1 diabetes (T1D) onset is possible if molecular triggering events can be pharmacologically targeted. The integrated stress response (ISR) is activated during cellular stress to halt protein production and redirect energy towards cellular survival temporarily. We hypothesized that the activity of the ISR in the insulin-producing β cell during T1D becomes maladaptive and renders the cell prone to autoimmunity. We show that suppression of the ISR by using a novel inhibitor of the kinase PERK reverses the translation initiation block in stressed human islets and delays the onset of diabetes, reduces islet inflammation, and preserves β cell mass in T1D-susceptible mice. Single-cell RNA sequencing of islets from PERK-inhibited mice shows reductions in the unfolded protein response and PERK signaling pathways and alterations in antigen processing and presentation pathways in β cells. Spatial proteomics analysis of islets from these mice shows a post-transcriptional increase in the immune checkpoint protein PD-L1 in β cells. Golgi membrane protein 1, whose levels increase following ISR inhibition in human islets and EndoC-βH1 human β cells, interacts with and post-transcriptionally stabilizes PD-L1. Collectively, our studies show that the ISR, mediated by PERK, enhances β cell immunogenicity, and inhibition of PERK may offer a strategy to prevent or delay the development of T1D.
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| Overall design |
Female NOD mice were oral-gavaged with vehicle or 6 mg/kg HC-5770 (PERK inhibitor) for 2 weeks (6-8 weeks of age). At the end of the treatment, mouse islets were isolated following Stull et al., 2012 and samples were submitted for scRNAseq (n=3 biological replicates per group).
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| Contributor(s) |
Muralidharan C, Huang F, Enriquez JR, Wang JE, Nelson JB, Nargis T, May SC, Chakraborty A, Figatner KT, Navitskaya S, Anderson CM, Calvo V, Surguladze D, Mulvihill MJ, Yi X, Sarkar S, Oakes SA, Webb-Robertson BM, Sims EK, Staschke KA, Eizirik DL, Nakayasu ES, Stokes ME, Tersey SA, Mirmira RG |
| Citation(s) |
38889047 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| U01 DK127786 |
The Integrated Stress Response in Human Islets During Early T1D |
UNIVERSITY OF CHICAGO |
Bobbie-Jo Mary Webb-Robertson |
| P30 DK020595 |
Diabetes Research and Training Center |
UNIVERSITY OF CHICAGO |
Raghavendra G Mirmira |
| R01 DK060581 |
Transcriptional and Translational Mechanisms Governing Beta Cell Function |
UNIVERSITY OF CHICAGO |
Raghavendra G Mirmira |
| R01 DK133881 |
Implications of Changes in Islet Exosomal Cargo in Type 1 Diabetes |
INDIANA UNIVERSITY |
Raghavendra G Mirmira |
| U01 DK127786 |
The Integrated Stress Response in Human Islets During Early T1D |
UNIVERSITY OF CHICAGO |
Raghavendra G Mirmira |
| U01 DK127786 |
The Integrated Stress Response in Human Islets During Early T1D |
UNIVERSITY OF CHICAGO |
Decio Laks Eizirik |
| R01 DK133881 |
Implications of Changes in Islet Exosomal Cargo in Type 1 Diabetes |
INDIANA UNIVERSITY |
Emily K Sims |
| R01 CA219815 |
Targeting the Unfolded Protein Response in PanNETs |
UNIVERSITY OF CHICAGO |
Scott A. Oakes |
| F31 DK134070 |
Hypusine as a nutrient-sensing modulator of eIF5A function in β cells |
UNIVERSITY OF CHICAGO |
Cara Anderson |
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| Submission date |
Oct 10, 2023 |
| Last update date |
Sep 24, 2024 |
| Contact name |
Raghavendra G Mirmira |
| E-mail(s) |
mirmira@uchicago.edu
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| Organization name |
University of Chicago
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| Department |
Medicine
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| Street address |
900 E 57th street
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| City |
Chicago |
| State/province |
IL |
| ZIP/Postal code |
60637 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA1026605 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE245004_Integrated_AllSamples_Vehicle_vs_HC5770.h5seurat |
4.7 Gb |
(ftp)(http) |
H5SEURAT |
| GSE245004_Raw_Counts_All_Samples.txt.gz |
374.6 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
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