Yeast Protein Kinase Ypk1, Human Ortholog SGK1, Contributes to ER Proteostasis
Mentor 1
Madhusudan Dey
Start Date
10-5-2022 10:00 AM
Description
Almost one-third of cellular proteins fold inside the endoplasmic reticulum (ER) to become their biologically active forms. If proteins misfold or unfold, they begin to accumulate in the ER lumen – a condition known as ER stress. This error of protein folding is toxic and can eventually lead to cell death. To alleviate the ER stress, the cell activates a network of signaling pathways called the unfolded protein response (UPR). A conserved UPR pathway is the Ire1 pathway from yeast to humans. During ER stress, Ire1 cleaves the HAC1 mRNA in yeast cells or XBP1 mRNA in human cells to remove an intervening sequence, resulting expression of Hac1 or Xbp1 protein. Hac1/Xbp1 is a transcription factor that activates the expression protein folding enzymes and chaperones that enhance the protein folding capacity of cells. Recently, our lab identified that the yeast protein kinase Ypk1 contributes to the Ire1-mediated Hac1 mRNA and splicing and translation. Ypk1 is a homolog of the human serum and glucocorticoid-induced protein kinase 1 (SGK1). We have found that inhibition of SGK1 resulted in reduction of Xbp1 mRNA splicing in human embryonic kidney cells (HEK293). Together, our data provides evidence that the protein kinase Ypk1 and its human ortholog SGK1 contribute to the Ire1-HAC/XBP1 mediated ER stress response.
Yeast Protein Kinase Ypk1, Human Ortholog SGK1, Contributes to ER Proteostasis
Almost one-third of cellular proteins fold inside the endoplasmic reticulum (ER) to become their biologically active forms. If proteins misfold or unfold, they begin to accumulate in the ER lumen – a condition known as ER stress. This error of protein folding is toxic and can eventually lead to cell death. To alleviate the ER stress, the cell activates a network of signaling pathways called the unfolded protein response (UPR). A conserved UPR pathway is the Ire1 pathway from yeast to humans. During ER stress, Ire1 cleaves the HAC1 mRNA in yeast cells or XBP1 mRNA in human cells to remove an intervening sequence, resulting expression of Hac1 or Xbp1 protein. Hac1/Xbp1 is a transcription factor that activates the expression protein folding enzymes and chaperones that enhance the protein folding capacity of cells. Recently, our lab identified that the yeast protein kinase Ypk1 contributes to the Ire1-mediated Hac1 mRNA and splicing and translation. Ypk1 is a homolog of the human serum and glucocorticoid-induced protein kinase 1 (SGK1). We have found that inhibition of SGK1 resulted in reduction of Xbp1 mRNA splicing in human embryonic kidney cells (HEK293). Together, our data provides evidence that the protein kinase Ypk1 and its human ortholog SGK1 contribute to the Ire1-HAC/XBP1 mediated ER stress response.
