Janus Kinase 1 Is Required for Transcriptional Reprograming of Murine Astrocytes in Response to Endoplasmic Reticulum Stress
Neurodegenerative diseases are associated with the accumulation of misfolded proteins in the endoplasmic reticulum (ER), leading to ER stress. To adapt, cells initiate the unfolded protein response (UPR). However, severe or unresolved UPR activation leads to cell death and inflammation. The UPR is i...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-10-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fncel.2019.00446/full |
| _version_ | 1818985270771449856 |
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| author | Savannah G. Sims Gordon P. Meares Gordon P. Meares Gordon P. Meares |
| author_facet | Savannah G. Sims Gordon P. Meares Gordon P. Meares Gordon P. Meares |
| author_sort | Savannah G. Sims |
| collection | DOAJ |
| description | Neurodegenerative diseases are associated with the accumulation of misfolded proteins in the endoplasmic reticulum (ER), leading to ER stress. To adapt, cells initiate the unfolded protein response (UPR). However, severe or unresolved UPR activation leads to cell death and inflammation. The UPR is initiated, in part, by the trans-ER membrane kinase PKR-like ER kinase (PERK). Recent evidence indicates ER stress and inflammation are linked, and we have shown that this involves PERK-dependent signaling via Janus Kinase (JAK) 1. This signaling provokes the production of soluble inflammatory mediators such as interleukin-6 (IL-6) and chemokine C-C motif ligand 2 (CCL2). We, therefore, hypothesized that JAK1 may control widespread transcriptional changes in response to ER stress. Here, using RNA sequencing of primary murine astrocytes, we demonstrate that JAK1 regulates approximately 10% of ER stress-induced gene expression and is required for a subset of PERK-dependent genes. Additionally, ER stress synergizes with tumor necrosis factor-α (TNF-α) to drive inflammatory gene expression in a JAK1-dependent fashion. We identified that JAK1 contributes to activating transcription factor (ATF) 4-dependent gene expression, including expression of the genes growth arrest and DNA damage (GADD) 45α and tribbles (TRIB) 3 that have not previously been associated with JAK signaling. While these genes are JAK1 dependent in response to ER stress, expression of GADD45α and TRIB3 are not induced by the JAK1-activating cytokine, oncostatin M (OSM). Transcriptomic analysis revealed that JAK1 drives distinct transcriptional programs in response to OSM stimulation versus ER stress. Interestingly, JAK1-dependent genes induced by ER stress in an ATF4-dependent mechanism were unaffected by small molecule inhibition of JAK1, suggesting that, in response to UPR activation, JAK1 initiates gene expression using non-canonical mechanisms. Overall, we have identified that JAK1 is a major regulator of ER stress-induced gene expression. |
| first_indexed | 2024-12-20T18:32:14Z |
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| id | doaj.art-1ee6647be84b4fd2b1f2c2e4ee693925 |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-12-20T18:32:14Z |
| publishDate | 2019-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-1ee6647be84b4fd2b1f2c2e4ee6939252022-12-21T19:30:01ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022019-10-011310.3389/fncel.2019.00446476859Janus Kinase 1 Is Required for Transcriptional Reprograming of Murine Astrocytes in Response to Endoplasmic Reticulum StressSavannah G. Sims0Gordon P. Meares1Gordon P. Meares2Gordon P. Meares3Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, WV, United StatesDepartment of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, WV, United StatesDepartment of Neuroscience, West Virginia University, Morgantown, WV, United StatesRockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, United StatesNeurodegenerative diseases are associated with the accumulation of misfolded proteins in the endoplasmic reticulum (ER), leading to ER stress. To adapt, cells initiate the unfolded protein response (UPR). However, severe or unresolved UPR activation leads to cell death and inflammation. The UPR is initiated, in part, by the trans-ER membrane kinase PKR-like ER kinase (PERK). Recent evidence indicates ER stress and inflammation are linked, and we have shown that this involves PERK-dependent signaling via Janus Kinase (JAK) 1. This signaling provokes the production of soluble inflammatory mediators such as interleukin-6 (IL-6) and chemokine C-C motif ligand 2 (CCL2). We, therefore, hypothesized that JAK1 may control widespread transcriptional changes in response to ER stress. Here, using RNA sequencing of primary murine astrocytes, we demonstrate that JAK1 regulates approximately 10% of ER stress-induced gene expression and is required for a subset of PERK-dependent genes. Additionally, ER stress synergizes with tumor necrosis factor-α (TNF-α) to drive inflammatory gene expression in a JAK1-dependent fashion. We identified that JAK1 contributes to activating transcription factor (ATF) 4-dependent gene expression, including expression of the genes growth arrest and DNA damage (GADD) 45α and tribbles (TRIB) 3 that have not previously been associated with JAK signaling. While these genes are JAK1 dependent in response to ER stress, expression of GADD45α and TRIB3 are not induced by the JAK1-activating cytokine, oncostatin M (OSM). Transcriptomic analysis revealed that JAK1 drives distinct transcriptional programs in response to OSM stimulation versus ER stress. Interestingly, JAK1-dependent genes induced by ER stress in an ATF4-dependent mechanism were unaffected by small molecule inhibition of JAK1, suggesting that, in response to UPR activation, JAK1 initiates gene expression using non-canonical mechanisms. Overall, we have identified that JAK1 is a major regulator of ER stress-induced gene expression.https://www.frontiersin.org/article/10.3389/fncel.2019.00446/fullinflammationastrocytesunfolded protein responseprotein misfoldingneurodegenerationJanus kinase |
| spellingShingle | Savannah G. Sims Gordon P. Meares Gordon P. Meares Gordon P. Meares Janus Kinase 1 Is Required for Transcriptional Reprograming of Murine Astrocytes in Response to Endoplasmic Reticulum Stress Frontiers in Cellular Neuroscience inflammation astrocytes unfolded protein response protein misfolding neurodegeneration Janus kinase |
| title | Janus Kinase 1 Is Required for Transcriptional Reprograming of Murine Astrocytes in Response to Endoplasmic Reticulum Stress |
| title_full | Janus Kinase 1 Is Required for Transcriptional Reprograming of Murine Astrocytes in Response to Endoplasmic Reticulum Stress |
| title_fullStr | Janus Kinase 1 Is Required for Transcriptional Reprograming of Murine Astrocytes in Response to Endoplasmic Reticulum Stress |
| title_full_unstemmed | Janus Kinase 1 Is Required for Transcriptional Reprograming of Murine Astrocytes in Response to Endoplasmic Reticulum Stress |
| title_short | Janus Kinase 1 Is Required for Transcriptional Reprograming of Murine Astrocytes in Response to Endoplasmic Reticulum Stress |
| title_sort | janus kinase 1 is required for transcriptional reprograming of murine astrocytes in response to endoplasmic reticulum stress |
| topic | inflammation astrocytes unfolded protein response protein misfolding neurodegeneration Janus kinase |
| url | https://www.frontiersin.org/article/10.3389/fncel.2019.00446/full |
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