Cleavage by Caspase 8 and Mitochondrial Membrane Association Activate the BH3-only Protein Bid during TRAIL-induced Apoptosis
Open accessAbstract
The BH3-only protein Bid is known as a critical mediator of the mitochondrial pathway of apoptosis following death receptor activation. However, since full-length Bid possesses potent apoptotic activity, the role of a caspase-mediated Bid cleavage is not established in vivo In addition, due to the fact that multiple caspases cleave Bid at the same site in vitro, the identity of the Bid-cleaving caspase during death receptor signaling remains uncertain. Moreover, as Bid maintains its overall structure following its cleavage by caspase 8, it remains unclear how Bid is activated upon cleavage. Here, Bid-deficient (Bid KO) colon cancer cells were generated by gene editing, and were reconstituted with wild-type or mutants of Bid. While the loss of Bid blocked apoptosis following treatment by TNF-related apoptosis inducing ligand (TRAIL), this blockade was relieved by re-introduction of the wild-type Bid. In contrast, the caspase-resistant mutant Bid(D60E) and a BH3 defective mutant Bid(G94E) failed to restore TRAIL-induced apoptosis. By generating Bid/Bax/Bak-deficient (TKO) cells, we demonstrated that Bid is primarily cleaved by caspase 8, not by effector caspases, to give rise to truncated Bid (tBid) upon TRAIL treatment. Importantly, despite the presence of an intact BH3 domain, a tBid mutant lacking the mitochondrial targeting helices (α6 and α7) showed diminished apoptotic activity. Together, these results for the first time establish that cleavage by caspase 8 and the subsequent association with the outer mitochondrial membrane are two critical events that activate Bid during death receptor-mediated apoptosis.
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Cleavage of BID by CASP8 leads to generation of tBID, which translocates to OMM.
“This leads to the generation of a truncated form of BID (tBID), which translocates to the OMM [313, 314]”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [314]
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- Authors
- Huang, K., Zhang, J., O’Neill, K. L., Gurumurthy, C. B., Quadros, R. M., Tu, Y., & Luo, X.
- Affiliations
- University of Nebraska Medical Center (US)
- Central South University (CN)
- Creighton University (US)
- Corresponding author
- Luo, Xu
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2016-05
- Volume
- 291
- Issue
- 22
- Pages
- 11843-11851
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4882451
- OpenAlex
- W2398317311
- Cited by
- 136
- References
- 47
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 23 · 2023: 13 · 2022: 11 · 2021: 18 · 2020: 10 · 2019: 11 · 2018: 14 · 2017: 13 · 2016: 1
- FWCI
- 6.72
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Creighton Digital Repository (CDR) (submittedVersion)
- Funders
- National Institutes of Health (1R21CA193271)
- National Institute of General Medical Sciences (P30 GM106397)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Social Sciences › Anthropology › Death, Funerary Practices, and Mourning
- Keywords
- Bid, caspase-8, TRAIL, apoptosis, BH3-only proteins, truncated Bid, death receptor signaling, Bax, Bak, colon cancer cells
- MeSH terms
- Base Sequence, Colonic Neoplasms, Humans, Molecular Sequence Data, Peptide Fragments, Proto-Oncogene Proteins, Sequence Homology, Nucleic Acid, Tumor Cells, Cultured, Blotting, Western, Apoptosis, bcl-2 Homologous Antagonist-Killer Protein, BH3 Interacting Domain Death Agonist Protein, bcl-2-Associated X Protein, Mitochondrial Membranes, Caspase 8, TNF-Related Apoptosis-Inducing Ligand
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