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Key Roles of the Proteasome in Cell Protection

Alfred L. Goldberg, Department of Cell Biology, Harvard Medical School, Boston, MA

   Most proteins in mammalian cells are degraded by the ubiquitin-proteasome pathway, where protein substrates are linked to ubiquitin molecules by one of the cell’s many ubiquitin ligases (E3s).  This modification marks the protein for rapid degradation by the 26S proteasome.  This large complex uses ATP to unfold the proteins and to inject them into its 20S core particle, where they are digested to small peptides.  This system selectively destroys abnormally folded proteins as result from mutations and postsynthetic damage by heat or oxygen radicals.  Such proteins accumulate in various neurodegenerative diseases, and this pathway is critical in homeostasis and rapidly destroys many regulatory proteins, important in the control of gene expression and growth.

            Peptides released by proteasomes range from 2-24 residues in length.  Although most are rapidly digested to amino acids, some are transported through the ER to the cell surface, where they are presented to the immune system on MHC Class I molecules.  This process enables circulating cytotoxic T cells to screen for and eliminate virally infected cells and cancers.

With denervation, inactivity (e.g. bed rest or in space personnel due to lack of gravity) in many systemic diseases (e.g. cancer) and fasting, muscles atrophy due to a general activation of the ubiquitin-proteasome pathway in muscles.  The atrophying muscles show a common pattern of changes in expression of specific genes (which we term “atrogenes”).  The two proteins induced most dramatically are muscle-specific ubiquitin ligases, atrogin-1 and MuRF-1, which are essential in the atrophy process and the accelerated proteolysis.  In atrophying muscles, the Foxo family of transcription factors transcribes atrogin and triggers muscle wasting.  Therefore, inhibitors of Foxo activation or the ubiquitin-proteasome pathway are an attractive approach to combat muscle wasting.

            Much has been learned about the functions of this ubiquitin-proteasome system by the use of inhibitors of the proteasome that enter cells and inhibit intracellular proteolysis.  Blocking proteasome function eventually induces apoptosis, especially in cancer cells.  One such inhibitor (Velcade PS341) has been approved by the FDA for treatment of multiple myeloma, but it is now in many phase II trials against diverse cancers.