Janus Kinase 1 is required for transcriptional reprogramming in response to endoplasmic reticulum stress

Neurodegenerative diseases are associated with the accumulation of misfolded proteins in the endoplasmic reticulum (ER). ER stress occurs when the protein folding capacity of the ER is overwhelmed, resulting in the initiation of the unfolded protein response (UPR). However, 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 Janus Kinase (JAK) 1 signaling. This signaling provokes the production of soluble inflammatory mediators such as Interleukin-6 (IL-6) and chemokine C-C motif ligand 2 (CCL2). Here, we demonstrate that JAK1 regulates approximately 10% of ER stress-induced gene expression and is required for a subset of PERK-dependent genes. JAK1 regulates genes associated with inflammation and the UPR, including PERK, in response to ER stress. Moreover, using JAK1 siRNA knockdown and a JAK1/2 kinase inhibitor, AZD1480, we show that JAK1 modulates gene expression using both kinase-dependent and independent mechanisms during ER stress. JAK1 also relies on these mechanisms to drive synergistic gene expression between ER stress and tumor necrosis factor-a (TNF-a). Overall, we have identified JAK1 as a major driver of transcriptional adaptation in response to ER stress.