ER stress triggers apoptosis by activating BH3-only protein Bim.

By H. Puthalakath, L. O’Reilly, Priscilla Gunn, L. Lee, Priscilla N. Kelly, Nicholas D. Huntington, P. Hughes, Ewa M Michalak, J. McKimm-Breschkin, N. Motoyama and 4 more. Cell, 2007

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Endoplasmic reticulum (ER) stress caused by misfolded proteins or cytotoxic drugs can kill cells and although activation of this pathway has been implicated in the etiology of certain degenerative disorders its mechanism remains unresolved. Bim, a proapoptotic BH3-only member of the Bcl-2 family is required for initiation of apoptosis induced by cytokine deprivation or certain stress stimuli. Its proapoptotic activity can be regulated by several transcriptional or posttranslational mechanisms, such as ERK-mediated phosphorylation, promoting its ubiquitination and proteasomal degradation. We found that Bim is essential for ER stress-induced apoptosis in a diverse range of cell types both in culture and within the whole animal. ER stress activates Bim through two novel pathways, involving protein phosphatase 2A-mediated dephosphorylation, which prevents its ubiquitination and proteasomal degradation and CHOP-C/EBPalpha-mediated direct transcriptional induction. These results define the molecular mechanisms of ER stress-induced apoptosis and identify targets for therapeutic intervention in ER stress-related diseases.

Subfields: Cell Biology, Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/3929c5497b7e0735cd8cbb331cbffaf9059e7858

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Citations in the corpus

Autophagy and apoptosis dysfunction in neurodegenerative disorders. (2014, neutral): “Existence of a strong link between ER stress and induction of apoptosis has been previously demonstrated (Nakagawa et al., 2000; Puthalakath et al., 2007).”
Cell Death Signaling. (2015, background): “…Hsc70 Cell survival Matsui et al. 2007 ? mRNA stability miR-17-92 Cell survival Xiao et al. 2008 ER stress Transcription CHOP-C/EBPa Apoptosis Puthalakath et al. 2007 Dephosphorylation PP2A Apoptosis Puthalakath et al. 2007 Glucocorticoid Transcription GR Apoptosis Erlacher et al. 2005;…”
The Unfolded Protein Response and Cell Fate Control. (2017, neutral): “BIM, for example, is transcriptionally upregulated by PERK and its protein product is stabilized in response to ER stress (Puthalakath et al., 2007).”
BCL-2 family antagonists for cancer therapy (2008, background): “, is the primary responder to endoplasmic reticulum stress”
The impact of the unfolded protein response on human disease (2012, background): “, 2005), BIM (Puthalakath et al., 2007), and PUMA (Cazanave et al.”
Endoplasmic reticulum stress: molecular mechanism and therapeutic targets (2023, background): “40,41 Subsequently, mitochondrial outer membrane permeabilization facilitates the release of cytochrome c. 35 Bcl2 can also regulate BH3-only protein expressions (like BAX and BAK), which can bind to mitochondria and cause mitochondrial permeabilization.”
Metabolic control of cell death (2014, background): “BIM is further stabilized by the ER stressdependent activation of protein phosphatase 2A (PP2A), resulting in the inhibition of antiapoptotic BCL-2 proteins coupled to the activation of their pro-apoptotic counterparts and MOMP.”
Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities (2008, background): “In addition, recent data indicate that CHOP binds an element in the promoter of the gene encoding BIM proteins (pro-apoptotic members of the BCL-2 family”
Chondrocyte Apoptosis in the Pathogenesis of Osteoarthritis (2015, background): “The multi-domain pro-apoptotic members of the Bcl-2 family, such as Bax and Bak, which have BH1, BH2, BH3 and TM domains, are responsible for disruption of organellar membranes and induction of caspase activation, while the BH3-only pro-apoptotic members containing only the BH3 domain include Bid, B”