Increased proteasome activity in human embryonic stem cells is regulated by PSMD11 (original) (raw)

Nature volume 489, pages 304–308 (2012)Cite this article

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Abstract

Embryonic stem cells can replicate continuously in the absence of senescence and, therefore, are immortal in culture1,2. Although genome stability is essential for the survival of stem cells, proteome stability may have an equally important role in stem-cell identity and function. Furthermore, with the asymmetric divisions invoked by stem cells, the passage of damaged proteins to daughter cells could potentially destroy the resulting lineage of cells. Therefore, a firm understanding of how stem cells maintain their proteome is of central importance. Here we show that human embryonic stem cells (hESCs) exhibit high proteasome activity that is correlated with increased levels of the 19S proteasome subunit PSMD11 (known as RPN-6 in Caenorhabditis elegans)3,4,5 and a corresponding increased assembly of the 26S/30S proteasome. Ectopic expression of PSMD11 is sufficient to increase proteasome assembly and activity. FOXO4, an insulin/insulin-like growth factor-I (IGF-I) responsive transcription factor associated with long lifespan in invertebrates6,7, regulates proteasome activity by modulating the expression of PSMD11 in hESCs. Proteasome inhibition in hESCs affects the expression of pluripotency markers and the levels of specific markers of the distinct germ layers. Our results suggest a new regulation of proteostasis in hESCs that links longevity and stress resistance in invertebrates to hESC function and identity.

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Acknowledgements

We thank W. E. Balch for critical comments on this work. We thank A. Stauffer and V. Modesto for their help with BrdU assays and cell culture, respectively. We thank S. Ruiz for advice on hESC culture and lentiviral infection. This work was supported by the Howard Hughes Medical Institute. D.V. was a recipient of the F.M. Kirby, Inc. Foundation Postdoctoral Scholar Award and Beatriu de Pinós (AGAUR) fellowship. F.H.G. acknowledges the Helmsley Foundation, JPB Foundation, Mathers Foundation, Lookout Fund and California Institute for Regenerative Medicine.

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Authors and Affiliations

  1. Howard Hughes Medical Institute, Glenn Center for Aging Research, Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA ,
    David Vilchez, Ianessa Morantte, Carsten Merkwirth, Derek Joyce & Andrew Dillin
  2. Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA ,
    Leah Boyer & Fred H. Gage
  3. Stem Cell Core, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA ,
    Margaret Lutz & W. Travis Berggren
  4. Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA,
    Brian Spencer & Eliezer Masliah
  5. Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA,
    Lesley Page

Authors

  1. David Vilchez
  2. Leah Boyer
  3. Ianessa Morantte
  4. Margaret Lutz
  5. Carsten Merkwirth
  6. Derek Joyce
  7. Brian Spencer
  8. Lesley Page
  9. Eliezer Masliah
  10. W. Travis Berggren
  11. Fred H. Gage
  12. Andrew Dillin

Contributions

D.V. and A.D. planned and supervised the project. D.V. performed the experiments, data analysis and interpretation. L.B. performed neural differentiation assays and contributed to other assays. I.M. performed biochemistry experiments and contributed to other assays. M.L. performed cell culturing and trophoblast/fibroblast differentiation. C.M. performed biochemistry experiments and contributed to other assays. D.J. performed proteasome assembly experiments. B.S., L.P. and E.M. generated lentiviral constructs. W.T.B. and F.H.G. contributed with their knowledge of stem-cell biology and neural differentiation, and helped to supervise the project. The manuscript was written by D.V. and A.D. and edited by L.B., I.M., C.M., W.T.B. and F.H.G. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence toAndrew Dillin.

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The authors declare no competing financial interests.

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Vilchez, D., Boyer, L., Morantte, I. et al. Increased proteasome activity in human embryonic stem cells is regulated by PSMD11.Nature 489, 304–308 (2012). https://doi.org/10.1038/nature11468

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Editorial Summary

Proteasome linked to stem cells' longevity

Two manuscripts in this issue of Nature converge on the role of the proteasome in longevity and stem-cell function. The first establishes a possible mechanism to explain why the removal of proliferating germline cells in the roundworm Caenorhabditis elegans extends lifespan. Worms with the glp-1(e2141) mutation lack a germ line and reallocate resources to the soma, potentially freeing up resources to invest in lifespan extension. These mutants also have sixfold higher proteasome activity than their normal counterparts, as well as increased clearance of damaged proteins associated with raised expression of the rpn-6 subunit of the 19S proteasome and the FOXO transcription factor DAF-16. Ectopic expression of rpn-6 is sufficient to extend lifespan and to protect against proteotoxic stress, suggesting that rpn-6 is a candidate to correct deficiencies in age-related protein-homeostasis disorders. The second paper starts with the hypothesis that rapidly dividing stem cells have high proteasome activity to safeguard the integrity of the genome and proteome by removing damaged proteins. Human embryonic stem cells are shown to exhibit high 26S/30S proteasome activity that decreases on induced differentiation. The high proteasome activity is due to increased expression of the 19S subunit PSMD11/RPN-6 and the modulation of its expression by FOXO4, an insulin/IGF-1-responsive transcription factor and DAF-16 orthologue.