Cho, Ukrae H.; Hetzer, MartinISTA
During apoptosis, caspases degrade 8 out of ~30 nucleoporins to irreversibly demolish the nuclear pore complex. However, for poorly understood reasons, caspases are also activated during cell differentiation. Here, we show that sublethal activation of caspases during myogenesis results in the transient proteolysis of four peripheral Nups and one transmembrane Nup. ‘Trimmed’ NPCs become nuclear export-defective, and we identified in an unbiased manner several classes of cytoplasmic, plasma membrane, and mitochondrial proteins that rapidly accumulate in the nucleus. NPC trimming by non-apoptotic caspases was also observed in neurogenesis and endoplasmic reticulum stress. Our results suggest that caspases can reversibly modulate nuclear transport activity, which allows them to function as agents of cell differentiation and adaptation at sublethal levels.
We thank the members of the Hetzer laboratory, Tony Hunter (Salk), Lorenzo Puri (Sanford Burnham Prebys), and Jongmin Kim (Massachusetts General Hospital) for the critical reading of the manuscript; Kenneth Diffenderfer and Aimee Pankonin (Stem Cell Core at the Salk Institute) for help with neurogenesis; Carol Marchetto and Fred Gage (Salk) for providing H9 embryonic stem cells; Lorenzo Puri, Alexandra Sacco, and Luca Caputo (Sanford Burnham Prebys) for helpful discussions and sharing mouse primary myoblasts. This work was supported by a Glenn Foundation for Medical Research Postdoctoral Fellowship in Aging Research (UHC), the NOMIS foundation (MWH), and the National Institutes of Health (R01 NS096786 to MWH and K01 AR080828 to UHC). This work was also supported by the Mass Spectrometry Core of the Salk Institute with funding from NIH-NCI CCSG: P30 014195 and the Helmsley Center for Genomic Medicine. We thank Jolene Diedrich and Antonio Pinto for technical support.
Cho UH, Hetzer M. Caspase-mediated nuclear pore complex trimming in cell differentiation and endoplasmic reticulum stress. eLife. 2023;12. doi:10.7554/eLife.89066
Cho, U. H., & Hetzer, M. (2023). Caspase-mediated nuclear pore complex trimming in cell differentiation and endoplasmic reticulum stress. ELife. eLife Sciences Publications. https://doi.org/10.7554/eLife.89066
Cho, Ukrae H., and Martin Hetzer. “Caspase-Mediated Nuclear Pore Complex Trimming in Cell Differentiation and Endoplasmic Reticulum Stress.” ELife. eLife Sciences Publications, 2023. https://doi.org/10.7554/eLife.89066.
U. H. Cho and M. Hetzer, “Caspase-mediated nuclear pore complex trimming in cell differentiation and endoplasmic reticulum stress,” eLife, vol. 12. eLife Sciences Publications, 2023.
Cho UH, Hetzer M. 2023. Caspase-mediated nuclear pore complex trimming in cell differentiation and endoplasmic reticulum stress. eLife. 12, RP89066.
Cho, Ukrae H., and Martin Hetzer. “Caspase-Mediated Nuclear Pore Complex Trimming in Cell Differentiation and Endoplasmic Reticulum Stress.” ELife, vol. 12, RP89066, eLife Sciences Publications, 2023, doi:10.7554/eLife.89066.
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