Ipomoeassin F Binds Sec61α to Inhibit Protein Translocation
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Abstract
Ipomoeassin F is a potent natural cytotoxin that inhibits growth of many tumor cell lines with single-digit nanomolar potency. However, its biological and pharmacological properties have remained largely unexplored. Building upon our earlier achievements in total synthesis and medicinal chemistry, we used chemical proteomics to identify Sec61α (protein transport protein Sec61 subunit alpha isoform 1), the pore-forming subunit of the Sec61 protein translocon, as a direct binding partner of ipomoeassin F in living cells. The interaction is specific and strong enough to survive lysis conditions, enabling a biotin analogue of ipomoeassin F to pull down Sec61α from live cells, yet it is also reversible, as judged by several experiments including fluorescent streptavidin staining, delayed competition in affinity pulldown, and inhibition of TNF biogenesis after washout. Sec61α forms the central subunit of the ER protein translocation complex, and the binding of ipomoeassin F results in a substantial, yet selective, inhibition of protein translocation in vitro and a broad ranging inhibition of protein secretion in live cells. Lastly, the unique resistance profile demonstrated by specific amino acid single-point mutations in Sec61α provides compelling evidence that Sec61α is the primary molecular target of ipomoeassin F and strongly suggests that the binding of this natural product to Sec61α is distinctive. Therefore, ipomoeassin F represents the first plant-derived, carbohydrate-based member of a novel structural class that offers new opportunities to explore Sec61α function and to further investigate its potential as a therapeutic target for drug discovery.
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Ipomoeassin F, eeyarestatin, and decatransin inhibit both the eukaryotic Sec61 complex and the bacterial SecYEG complex.
“Components that inhibit both the eukaryotic Sec61 complex and the bacterial SecYEG complex are the glycoresin Ipomoeassin F (IpomF) (Zong et al., 2019; Steinberg et al., 2020), eeyarestatin (Cross et al., 2009; Steenhuis et al., 2021) and decatransin (Junne et al., 2015; Kalies and Römisch, 2015).”
From The Dynamic SecYEG Translocon (2021) · cites this paper as Zong et al., 2019
IpomF inhibits SecYEG-dependent transport in vitro, but this requires significantly higher concentrations than required for inhibition of Sec61-dependent transport.
“IpomF also inhibits SecYEG-dependent transport in vitro, but this requires significantly higher concentrations than required for inhibition of Sec61-dependent transport (Zong et al., 2019; Steinberg et al., 2020).”
From The Dynamic SecYEG Translocon (2021) · cites this paper as Zong et al., 2019
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- Authors
- Zong, G., Hu, Z., O’Keefe, S., Tranter, D., Iannotti, M. J., Baron, L., Hall, B., Corfield, K., Paatero, A. O., Henderson, M. J., Roboti, P., Zhou, J., Sun, X., Govindarajan, M., Rohde, J. M., Blanchard, N., Simmonds, R., Inglese, J., Du, Y., Demangel, C., High, S., Paavilainen, V. O., & Shi, W. Q.
- Affiliations
- University of Maryland, College Park (US)
- University of Arkansas at Fayetteville (US)
- University of Manchester (GB)
- University of Helsinki (FI)
- National Institutes of Health (US)
- Inserm (FR)
- University of Surrey (GB)
- Baylor College of Medicine (US)
- Emory University (US)
- Centre National de la Recherche Scientifique (FR)
- Ball State University (US)
- Corresponding author
- Simmonds, Rachel
- Inglese, James
- Du, Yuchun
- Demangel, Caroline
- High, Stephen
- Paavilainen, Ville O.
- Shi, Wei Q.
- ORCID
- Zong, Guanghui
- Hu, Zhijian
- O’Keefe, Sarah
- Tranter, Dale
- Iannotti, Michael J.
- Baron, Ludivine
- Hall, Belinda
- Paatero, Anja O.
- Henderson, Mark J.
- Roboti, Peristera
- Zhou, Jianhong
- Rohde, Jason M.
- Blanchard, Nicolas
- Simmonds, Rachel
- Inglese, James
- Du, Yuchun
- Demangel, Caroline
- High, Stephen
- Paavilainen, Ville O.
- Shi, Wei Q.
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-05-06
- Volume
- 141
- Issue
- 21
- Pages
- 8450-8461
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- PMC
- PMC6627486
- OpenAlex
- W2943937786
- Cited by
- 93
- References
- 62
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 13 · 2023: 18 · 2022: 11 · 2021: 18 · 2020: 11 · 2019: 2
- FWCI
- 4.27
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of the American Chemical Society (publishedVersion, cc-by)
- ChemRxiv (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion, other-oa)
- HAL (submittedVersion, other-oa)
- Surrey Research Insight Open Access (The University of Surrey) (submittedVersion)
- Royal College of Surgeons in Ireland (submittedVersion, cc-by-nc-nd)
- Työväentutkimus Vuosikirja (submittedVersion)
- Funders
- National Institute of General Medical Sciences (P30 GM103450, R15 GM116032)
- Wellcome Trust (202843/Z/16/Z, 204957/Z/16/Z)
- National Center for Advancing Translational Sciences (1ZIA TR000048-03, ZIA TR000063-04)
- University of Arkansas (NA)
- Arkansas Biosciences Institute (NA)
- Institut National de la Santé et de la Recherche Médicale (NA)
- Suomen Akatemia (289737, 314672)
- Institut Pasteur (NA)
- Sigrid Juséliuksen Säätiö (NA)
- Fondation Raoul Follereau (NA)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Toxin Mechanisms and Immunotoxins
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Keywords
- Sec61α, endoplasmic reticulum, protein secretion, plant-derived natural products, chemoproteomics, molecular target identification, amino acid mutations, drug discovery targets
- MeSH terms
- SEC Translocation Channels, Binding Sites, Glycoconjugates, Humans, Molecular Structure, Protein Transport
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