School of Medicine
Microbiology, Immunology, and Cell Biology
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 transER membrane kinase PKR-like ER kinase (PERK). Recent evidence indicates ER stress and inflammation are linked, and we have shown that this involves PERKdependent 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.
Digital Commons Citation
Sims, Savannah G. and Meares, Gordon P., "Janus Kinase 1 Is Required for Transcriptional Reprograming of Murine Astrocytes in Response to Endoplasmic Reticulum Stress" (2019). Faculty & Staff Scholarship. 1593.
Sims SG and Meares GP (2019) Janus Kinase 1 Is Required for Transcriptional Reprograming of Murine Astrocytes in Response to Endoplasmic Reticulum Stress. Front. Cell. Neurosci. 13:446. doi: 10.3389/fncel.2019.00446