Smac, a Mitochondrial Protein that Promotes Cytochrome c–Dependent Caspase Activation by Eliminating IAP Inhibition

Du, Chunying; Fang, Min; Li, Yucheng; Li, Lily; Wang, Xiaodong

doi:10.1016/s0092-8674(00)00008-8

Cited by 3,513Cell death mechanisms and regulationUbiquitin and proteasome pathwaysCancer-related Molecular Pathways

Smac, a Mitochondrial Protein that Promotes Cytochrome c–Dependent Caspase Activation by Eliminating IAP Inhibition

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Du, Chunying, Fang, Min, Li, Yucheng, Li, Lily, Wang, Xiaodong·2000·Cell

DOI 10.1016/s0092-8674(00)00008-8

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Abstract

We report here the identification of a novel protein, Smac, which promotes caspase activation in the cytochrome c/Apaf-1/caspase-9 pathway. Smac promotes caspase-9 activation by binding to inhibitor of apoptosis proteins, IAPs, and removing their inhibitory activity. Smac is normally a mitochondrial protein but is released into the cytosol when cells undergo apoptosis. Mitochondrial import and cleavage of its signal peptide are required for Smac to gain its apoptotic activity. Overexpression of Smac increases cells' sensitivity to apoptotic stimuli. Smac is the second mitochondrial protein, along with cytochrome c, that promotes apoptosis by activating caspases.

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MOMP directly promotes the cytosolic release of apoptogenic factors that normally reside in the mitochondrial intermembrane space, including cytochrome c (CYCS) and SMAC.
“MOMP directly promotes the cytosolic release of apoptogenic factors that normally reside in the mitochondrial intermembrane space [40, 44, 156]. These mitochondrial proteins include (but are not limited to) cytochrome c, somatic (CYCS), which usually operates as an electron shuttle in the mitochondrial respiratory chain [157–160], and diablo IAP-binding mitochondrial protein (DIABLO; also known as”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [163]
Cytosolic SMAC precipitates apoptosis by associating with members of the inhibitor of apoptosis (IAP) protein family, including XIAP.
“Cytosolic SMAC precipitates apoptosis by associating with members of the inhibitor of apoptosis (IAP) protein family, including X-linked inhibitor of apoptosis (XIAP) [162, 163, 181].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [163]

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Authors: Du, C., Fang, M., Li, Y., Li, L., & Wang, X.
Affiliations: Howard Hughes Medical Institute (US)
Corresponding author: Wang, Xiaodong
ORCID: Du, Chunying
Li, Yucheng
Li, Lily
Wang, Xiaodong
Venue: Cell
Publisher: Elsevier BV
Published: 2000-07
Volume: 102
Issue: 1
Pages: 33-42
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/s0092-8674(00)00008-8
OpenAlex: W2042409437
Cited by: 3,513
References: 33
Citations by year: 2026: 38 · 2025: 65 · 2024: 64 · 2023: 79 · 2022: 77 · 2021: 86 · 2020: 85 · 2019: 77 · 2018: 81 · 2017: 89 · 2016: 108 · 2015: 117 · 2014: 111 · 2013: 146 · 2012: 137
FWCI: 87.72
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 4764 d)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute of General Medical Sciences (GMRO1-57158)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords: Smac/DIABLO, mitochondrial proteins, caspase-9 activation, cytochrome c, Apaf-1, inhibitor of apoptosis proteins, apoptosis, mitochondrial protein import, signal peptide cleavage, cytosolic release, apoptosis sensitivity
MeSH terms: Adult, Amino Acid Sequence, Base Sequence, Carrier Proteins, Cloning, Molecular, Cytochrome c Group, Cytosol, Enzyme Activation, Enzyme Precursors, HeLa Cells, Humans, Mitochondria, Molecular Sequence Data, Protein Processing, Post-Translational, Proteins, Radiation Tolerance, Ultraviolet Rays, Apoptosis, DNA, Complementary, Caspases, Protein Sorting Signals, Mitochondrial Proteins, Intracellular Signaling Peptides and Proteins, Apoptosis Regulatory Proteins, X-Linked Inhibitor of Apoptosis Protein, Caspase 3, Caspase 9, Apoptotic Protease-Activating Factor 1

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Smac, a Mitochondrial Protein that Promotes Cytochrome c–Dependent Caspase Activation by Eliminating IAP Inhibition

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