Abstract
Adaptation to endoplasmic reticulum (ER) stress relies on activation of the unfolded protein response (UPR) and induction of autophagy. Indeed, cells die if ER stress is not countered by the UPR. Here we show in U937 cells that the ER stressors tunicamycin and thapsigargin cause increased expression of c-Jun N-terminal kinase 2 (JNK2), which allows regulation of the UPR, whose silencing or pharmacological inhibition delays BiP (immunoglobulin heavy-chain binding protein) upregulation, and causes earlier and greater expression of CCAAT/enhancer-binding protein-homologous protein (CHOP). Furthermore, we show that pharmacological inhibition or silencing of JNK2 causes accumulation of both p62 and the acidic compartment, caspase 3 activation and apoptosis. Our results reveal that JNK2 prevents accumulation of the acidic compartment in U937 cells undergoing autophagic flux and, by this mechanism, it keeps stressed cells alive. Our findings highlight a potential role for JNK2 in tumor cell survival, senescence and neurodegenerative diseases, in which ER stress, autophagy and lysosome activity are known to interplay.
Highlights
endoplasmic reticulum (ER) of the accumulation of misfolded proteins that cannot be degraded by the proteasome,[7,8,9,10] using the ER itself to provide the membrane needed for autophagosome formation
Previous studies indicated that c-Jun N-terminal kinase (JNK) activation may be linked to ER stress by inositol-requiring kinase 1 (IRE1),19 and that autophagy induction after ER stress relies on the IRE1JNK pathway.[7,8]
Sub-G1 events were studied by cytofluorimetry of cell cycle phases of cells fixed and stained with propidium iodide (PI): hypodiploid DNA events are discernable from the narrow peak of cells with diploid DNA content, and are considered to be indicative of apoptotic nuclei.[28]
Summary
ER of the accumulation of misfolded proteins that cannot be degraded by the proteasome,[7,8,9,10] using the ER itself to provide the membrane needed for autophagosome formation. Excess stimulation of autophagy, as in the case of the UPR, can activate the cell death machinery,[12,13] making it likely that UPR and autophagy are interlinked, sharing a cytoprotective role under basal conditions or metabolic stress, and taking on a cytocidial function after acute cell damage In this multistep and multifunctional crosstalk among organelles, the lysosomes appear highly dynamic, as they receive materials from trans-Golgi, endocytic and autophagic pathways.[14,15] They contain more than 50 hydrolases, which consent reuse of the breakdown products of the major cellular macromolecules. Temporal regulation of JNK may be a critical determinant of cellular responses: JNK1 transient activation, for example, promotes cell survival, whereas prolonged activation is known to mediate apoptosis.[27] To clarify this issue, we set out to investigate whether moderate ER stress, caused by opportune doses of tunicamycin (TN), an N-glycosylation inhibitor, or thapsigargin (TG), which inhibits ER Ca2 þ release, can promote cell survival. By this means we identified a JNK2dependent mechanism that appears to counter apoptotic cell death
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