Abstract:
: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.
journal_name
Mol Cell Bioljournal_title
Molecular and cellular biologyauthors
Upton JP,Austgen K,Nishino M,Coakley KM,Hagen A,Han D,Papa FR,Oakes SAdoi
10.1128/MCB.00013-08subject
Has Abstractpub_date
2008-06-01 00:00:00pages
3943-51issue
12eissn
0270-7306issn
1098-5549pii
MCB.00013-08journal_volume
28pub_type
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