Proteome-wide CETSA reveals diverse apoptosis-inducing mechanisms converging on an initial apoptosis effector stage at the nuclear periphery

Proteome-wide CETSA reveals diverse apoptosis-inducing mechanisms converging on an initial apoptosis effector stage at the nuclear periphery

Cell Reports

10.1016/j.celrep.2024.114784

https://doi.org/10.1016/j.celrep.2024.114784

Anderson Daniel Ramos, Ying Yu Liang, Olga Surova, Smaranda Bacanu, Marc-Antoine Gerault, Tamoghna Mandal, Sophia Ceder, Anette Langebäck, Albin Österroos, George A. Ward, Jonas Bergh, Klas G. Wiman, Sören Lehmann, Nayana Prabhu, Sara Lööf, Pär Nordlund

03 October 2024

Ramos, A. D., Liang, Y. Y., Surova, O., Bacanu, S., Gerault, M.-A., Mandal, T., Ceder, S., Langebäck, A., Österroos, A., Ward, G. A., Bergh, J., Wiman, K. G., Lehmann, S., Prabhu, N., Lööf, S., & Nordlund, P. (2024). Proteome-wide CETSA reveals diverse apoptosis-inducing mechanisms converging on an initial apoptosis effector stage at the nuclear periphery. Cell Reports, 43(10), 114784. https://doi.org/10.1016/j.celrep.2024.114784

Cellular phenotypes of apoptosis, as well as the activation of apoptosis caspase cascades, are well described. However, sequences and locations of early biochemical effector events after apoptosis initiation are still only partly understood. Here, we use integrated modulation of protein interaction states-cellular thermal shift assay (IMPRINTS-CETSA) to dissect the cellular biochemistry of early stages of apoptosis at the systems level. Using 5 families of cancer drugs and a new CETSA-based method to monitor the cleavage of caspase targets, we discover the initial biochemistry of the effector stage of apoptosis for all the studied drugs being focused on the peripheral nuclear region rather than the cytosol. Despite very different candidate apoptosis-inducing mechanisms of the drug families, as revealed by the CETSA data, they converge into related biochemical modulations in the peripheral nuclear region. This implies a higher control of the localization of the caspase cascades than previously anticipated and highlights the nuclear periphery as a critical vulnerability for cancer therapies.

Attribution 4.0 International (CC BY 4.0)

This research / project is supported by the National Research Foundation Singapore - National Research Foundation Investigatorship
Grant Reference no. : NRF-NRFI08-2022

This research / project is supported by the National Research Foundation Singapore - Competitive Research Programme
Grant Reference no. : NRF-CRP22-2019-0003

This research / project is supported by the Radiumhemmet's funds - NA
Grant Reference no. : NA

This research / project is supported by the Knut and Alice Wallenberg Foundation - NA
Grant Reference no. : NA

This research / project is supported by the Swedish Research Council - NA
Grant Reference no. : NA

This research / project is supported by the Swedish Cancer Society - NA
Grant Reference no. : NA

https://oar.a-star.edu.sg/communities-collections/articles/21513

2211-1247

Institute of Molecular and Cell Biology