Caspase-2 cleavage of BID is a critical apoptotic signal downstream of endoplasmic reticulum stress.

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 Biol

authors

Upton JP,Austgen K,Nishino M,Coakley KM,Hagen A,Han D,Papa FR,Oakes SA

doi

10.1128/MCB.00013-08

subject

Has Abstract

pub_date

2008-06-01 00:00:00

pages

3943-51

issue

12

eissn

0270-7306

issn

1098-5549

pii

MCB.00013-08

journal_volume

28

pub_type

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