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

Departments of Pathology, and Medicine, University of California, San Francisco, CA 94143, USA

^* To whom correspondence should be addressed. Email: scott.oakes{at}ucsf.edu.

	Abstract

Accumulation of misfolded proteins stresses the endoplasmic reticulum (ER) and triggers cell death through activation of the multidomain pro-apoptotic 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 (MEFs) 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 pre-mitochondrial protease that cleaves BID in response to ER stress, and show 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.