Caspase-2 cleavage of BID is a critical apoptotic signal downstream of endoplasmic reticulum stress.
The accumulation of misfolded proteins stresses the endoplasmic reticulum (ER) and triggers cell death through activation of the multidomain proapoptotic BCL-2 proteins BAX and BAK at the outer mitochondrial membrane. The signaling events that connect ER stress with the mitochondrial apoptotic machinery remain unclear, despite evidence that deregulation of this pathway contributes to cell loss in many human degenerative diseases. In order to "trap" and identify the apoptotic signals upstream of mitochondrial permeabilization, we challenged Bax-/- Bak-/- mouse embryonic fibroblasts with pharmacological inducers of ER stress. We found that ER stress induces proteolytic activation of the BH3-only protein BID as a critical apoptotic switch. Moreover, we identified caspase-2 as the premitochondrial protease that cleaves BID in response to ER stress and showed that resistance to ER stress-induced apoptosis can be conferred by inhibiting caspase-2 activity. Our work defines a novel signaling pathway that couples the ER and mitochondria and establishes a principal apoptotic effector downstream of ER stress.
Upton
John-Paul
JP
Department of Pathology, Medicine, University of California, San Francisco, California 94143, USA.
Austgen
Kathryn
K
Nishino
Mari
M
Coakley
Kristen M
KM
Hagen
Andrew
A
Han
Dan
D
Papa
Feroz R
FR
Oakes
Scott A
SA
D000818:Animals; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism*; D053143:Caspase 2 / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000235:genetics
D051023:BH3 Interacting Domain Death Agonist Protein; C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; C494815:Bid protein, mouse; D004268:DNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D053143:Caspase 2