An initial phase of JNK activation inhibits cell death early in the endoplasmic reticulum stress response.
Accumulation of unfolded proteins in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR). In mammalian cells, UPR signals generated by several ER-membrane-resident proteins, including the bifunctional protein kinase endoribonuclease IRE1α, control cell survival and the decision to execute apoptosis. Processing of XBP1 mRNA by the RNase domain of IRE1α promotes survival of ER stress, whereas activation of the mitogen-activated protein kinase JNK family by IRE1α late in the ER stress response promotes apoptosis. Here, we show that activation of JNK in the ER stress response precedes activation of XBP1. This activation of JNK is dependent on IRE1α and TRAF2 and coincides with JNK-dependent induction of expression of several antiapoptotic genes, including cIap1 (also known as Birc2), cIap2 (also known as Birc3), Xiap and Birc6 ER-stressed Jnk1(-/-) Jnk2(-/-) (Mapk8(-/-) Mapk9(-/-)) mouse embryonic fibroblasts (MEFs) display more pronounced mitochondrial permeability transition and increased caspase 3/7 activity compared to wild-type MEFs. Caspase 3/7 activity is also elevated in ER-stressed cIap1(-/-) cIap2(-/-) and Xiap(-/-) MEFs. These observations suggest that JNK-dependent transcriptional induction of several inhibitors of apoptosis contributes to inhibiting apoptosis early in the ER stress response.
Durham University, School of Biological and Biomedical Sciences, Durham DH1 3LE, United Kingdom.|Biophysical Sciences Institute, Durham University, Durham DH1 3LE, United Kingdom.|North East England Stem Cell Institute (NESCI), Life Bioscience Centre, International Centre for Life, Central Parkway, Newcastle Upon Tyne, NE1 4EP, UK.
Max
M
Brown
Durham University, School of Biological and Biomedical Sciences, Durham DH1 3LE, United Kingdom.|Biophysical Sciences Institute, Durham University, Durham DH1 3LE, United Kingdom.|North East England Stem Cell Institute (NESCI), Life Bioscience Centre, International Centre for Life, Central Parkway, Newcastle Upon Tyne, NE1 4EP, UK.
Natalie
N
Strudwick
Durham University, School of Biological and Biomedical Sciences, Durham DH1 3LE, United Kingdom.|Biophysical Sciences Institute, Durham University, Durham DH1 3LE, United Kingdom.|North East England Stem Cell Institute (NESCI), Life Bioscience Centre, International Centre for Life, Central Parkway, Newcastle Upon Tyne, NE1 4EP, UK.
Monika
M
Suwara
Durham University, School of Biological and Biomedical Sciences, Durham DH1 3LE, United Kingdom.|Biophysical Sciences Institute, Durham University, Durham DH1 3LE, United Kingdom.|North East England Stem Cell Institute (NESCI), Life Bioscience Centre, International Centre for Life, Central Parkway, Newcastle Upon Tyne, NE1 4EP, UK.
Louise K
LK
Sutcliffe
Durham University, School of Biological and Biomedical Sciences, Durham DH1 3LE, United Kingdom.|Biophysical Sciences Institute, Durham University, Durham DH1 3LE, United Kingdom.|North East England Stem Cell Institute (NESCI), Life Bioscience Centre, International Centre for Life, Central Parkway, Newcastle Upon Tyne, NE1 4EP, UK.
Adina D
AD
Mihai
Durham University, School of Biological and Biomedical Sciences, Durham DH1 3LE, United Kingdom.|Biophysical Sciences Institute, Durham University, Durham DH1 3LE, United Kingdom.|North East England Stem Cell Institute (NESCI), Life Bioscience Centre, International Centre for Life, Central Parkway, Newcastle Upon Tyne, NE1 4EP, UK.|Molecular Biology Department, National Research Centre, Dokki 12311, Cairo, Egypt.
Ahmed A
AA
Ali
Durham University, School of Biological and Biomedical Sciences, Durham DH1 3LE, United Kingdom.|Biophysical Sciences Institute, Durham University, Durham DH1 3LE, United Kingdom.|North East England Stem Cell Institute (NESCI), Life Bioscience Centre, International Centre for Life, Central Parkway, Newcastle Upon Tyne, NE1 4EP, UK.
Jamie N
JN
Watson
Durham University, School of Biological and Biomedical Sciences, Durham DH1 3LE, United Kingdom.|Biophysical Sciences Institute, Durham University, Durham DH1 3LE, United Kingdom.|North East England Stem Cell Institute (NESCI), Life Bioscience Centre, International Centre for Life, Central Parkway, Newcastle Upon Tyne, NE1 4EP, UK.
Martin
M
Schröder
D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D016923:Cell Death; D003600:Cytosol / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D004722:Endoribonucleases / Q000378:metabolism; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D000071717:X-Box Binding Protein 1 / Q000378:metabolism
D051034:Inhibitor of Apoptosis Proteins; D047992:TNF Receptor-Associated Factor 2; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D004722:Endoribonucleases
Apoptosis; Endoplasmic reticulum; IRE1; JNK; Stress response; Unfolded protein response