BH3-Only Protein BIM Mediates Heat Shock-Induced Apoptosis




Mahajan, Indra M.
Chen, Miao-Der
Muro, Isreal
Robertson, John D.
Wright, Casey W.
Bratton, Shawn B.

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Acute heat shock can induce apoptosis through a canonical pathway involving the upstream activation of caspase-2, followed by BID cleavage and stimulation of the intrinsic pathway. Herein, we report that the BH3-only protein BIM, rather than BID, is essential to heat shock-induced cell death. We observed that BIM-deficient cells were highly resistant to heat shock, exhibiting short and long-term survival equivalent to Bax−/−Bak−/− cells and better than either Bid−/− or dominant-negative caspase-9-expressing cells. Only Bim−/− and Bax−/−Bak−/− cells exhibited resistance to mitochondrial outer membrane permeabilization and loss of mitochondrial inner membrane potential. Moreover, while dimerized caspase-2 failed to induce apoptosis in Bid−/− cells, it readily did so in Bim−/− cells, implying that caspase-2 kills exclusively through BID, not BIM. Finally, BIM reportedly associates with MCL-1 following heat shock, and Mcl-1−/− cells were indeed sensitized to heat shock-induced apoptosis. However, pharmacological inhibition of BCL-2 and BCL-XL with ABT-737 also sensitized cells to heat shock, most likely through liberation of BIM. Thus, BIM mediates heat shock-induced apoptosis through a BAX/BAK-dependent pathway that is antagonized by antiapoptotic BCL-2 family members.


Indra M. Mahajan, Miao-Der Chen, Shawn B. Bratton, The University of Texas MD Anderson Cancer Center, Science Park, Department of Molecular Carcinogenesis, Smithville, Texas, United States of America
Indra M. Mahajan, Miao-Der Chen, Israel Muro, Casey W. Wright, Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas, United States of America
John D. Robertson, Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, United States of America

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Mahajan IM, Chen M-D, Muro I, Robertson JD, Wright CW, et al. (2014) BH3-Only Protein BIM Mediates Heat Shock-Induced Apoptosis. PLoS ONE 9(1): e84388. doi:10.1371/journal.pone.00843