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Mentions: Antiapoptotic Bcl-2 proteins have been found in the ER/nuclear envelope in addition to their localization in mitochondria (Krajewski et al., 1993; Akao et al., 1994; Nguyen et al., 1994). It remains unclear whether the proapoptotic proteins Bax and Bak also reside and function at the ER. Subcellular fractionation was performed in wild-type murine embryonic fibroblasts (MEFs), bax−/−bak−/− MEFs, and HeLa cells. In agreement with previous reports, Bax was found in the cytosolic S-100 fraction, as well as in the mitochondria fraction (heavy membrane [HM]). Bak was found in the mitochondrial fraction but not in the cytosol. Despite their differential appearance in the cytosol, both Bax and Bak were found in the ER/microsome fraction (light membrane [LM]) (Fig. 1Figure 1.
Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis
Bottom Line: In wild-type cells, this is associated with caspase 12 cleavage that is abolished in bax-/-bak-/- cells.In contrast, mitochondria-targeted Bak leads to enhanced caspase 7 and PARP cleavage in comparison with the ER-targeted Bak.These findings demonstrate that in addition to their functions at mitochondria, Bax and Bak also localize to the ER and function to initiate a parallel pathway of caspase activation and apoptosis.
Affiliation: Department of Cancer Biology, Abramson Cancer Center, 421 Curie Blvd., BRB II/III, 445, Philadelphia, PA 19104-6160, USA. email@example.com
Bax and Bak play a redundant but essential role in apoptosis initiated by the mitochondrial release of apoptogenic factors. In addition to their presence at the mitochondrial outer membrane, Bax and Bak can also localize to the ER. Agents that initiate ER stress responses can induce conformational changes and oligomerization of Bax on the ER as well as on mitochondria. In wild-type cells, this is associated with caspase 12 cleavage that is abolished in bax-/-bak-/- cells. In bax-/-bak-/- cells, introduction of Bak mutants selectively targeted to either mitochondria or the ER can induce apoptosis. However, ER-targeted, but not mitochondria-targeted, Bak leads to progressive depletion of ER Ca2+ and induces caspase 12 cleavage. In contrast, mitochondria-targeted Bak leads to enhanced caspase 7 and PARP cleavage in comparison with the ER-targeted Bak. These findings demonstrate that in addition to their functions at mitochondria, Bax and Bak also localize to the ER and function to initiate a parallel pathway of caspase activation and apoptosis.
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