Endoplasmic reticulum and cellular stress–induced apoptosis.
The endoplasmic reticulum regulates protein synthesis, N-linked glycosylation, trafficking, and intracellular Ca++ levels. Alterations in homeostasis such as induced by cellular stress induce the unfolded protein response and the ER overload response pathways, which may cope with incorrectly folded proteins in the ER but may also contribute to its elimination when abnormalities become too intensive. The unfolded protein response pathway leads to induction of chaperones such as grp78/Bip via the transcription factor CHOP/GADD153. The ER overload response pathway leads to production of cytokines via NF-κB. Several ER membrane proteins interact with Bcl-2 family members, such as the antiapoptotic Bax inhibitor I and Bap31 and the proapoptoticS pombe calnexin chaperone homolog Cnx1, the reticulon proteins (RTN) NSP-C/RTN1-C, and RTN-XS, or the calcium pump SERCA. Calreticulin, an ER luminal protein, promotes the release of cytochrome c from mitochondria, caspase-3 activity, and DNA fragmentation. Stress in the ER also activates JNKs in several cell types. Thus, the ER, via specific components of its luminal environment, may play an important role in the modulation of cell sensitivity to apoptosis.
