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A proteolytic system that compensates for loss of proteasome function

Nature volume 392, pages 618–622 (1998)Cite this article

Abstract

Proteolysis is essential for the execution of many cellular functions. These include removal of incorrectly folded or damaged proteins1, the activation of transcription factors2, the ordered degradation of proteins involved in cell cycle control3, and the generation of peptides destined for presentation by class I molecules of the major histocompatibility complex4. A multisubunit protease complex, the proteasome5, accomplishes these tasks. Here we show that in mammalian cells inactivation of the proteasome by covalent inhibitors allows the outgrowth of inhibitor-resistant cells. The growth of such adapted cells is apparently maintained by the induction of other proteolytic systems that compensate for the loss of proteasomal activity.

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Figure 1: Covalent modification of proteasomes in EL-4 cells cultured in the presence of NLVS blocks enzymatic activity.
Figure 2: Peptidase activity from EL-4-adapted and control fractions resolved by gel filtration (see Methods).
Figure 3: Synthesis and assembly of proteasome subunits is normal in adapted cells.
Figure 4: Adapted EL-4 cells generate ligands for stable assembly and intracellular transport of MHC class I molecules.
Figure 5: AAF-MCA hydrolysis is increased in adapted cells.
Figure 6: AAF-MCA hydrolysing activity elutes before the proteasome, indicating that it has a higher M r.

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Acknowledgements

This work was supported by grants from the NIH and Boehringer Ingelheim. R. G. is a fellow of the The Swedish Foundation for International Cooperation in Research and High Education (STINT) Stockholm.

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Author notes

  1. Rickard Glas, Matthew Bogyo & Hidde L. Ploegh

    Present address: Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts, 02115, USA

  2. John S. McMaster

    Present address: University of Utah Department of Biochemistry, Salt Lake City, Utah, 84132, USA

  3. Maria Gaczynska

    Present address: Department of Molecular Medicine, Institute of Biotechnology, Univesity of Texas Health Science Center, San Antonio, Texas, 78245, USA

  4. Rickard Glas and Matthew Bogyo: These authors contributed equally to this work

Authors and Affiliations

  1. Department for Biology, Center for Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, 02139-4307, Massachusetts, USA

    Rickard Glas, Matthew Bogyo, John S. McMaster, Maria Gaczynska & Hidde L. Ploegh

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  1. Rickard Glas
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Correspondence to Hidde L. Ploegh.

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Glas, R., Bogyo, M., McMaster, J. et al. A proteolytic system that compensates for loss of proteasome function. Nature 392, 618–622 (1998). https://doi.org/10.1038/33443

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