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Published July 2012 | public
Journal Article

The Ubiquitin System, an Immense Realm


Among the functions of intracellular proteolysis are the elimination of misfolded or otherwise abnormal proteins; the maintenance of amino acid pools in cells affected by stresses, such as starvation; and the generation of protein fragments that act as hormones, antigens, or other effectors. Many intracellular proteins are either conditionally or constitutively short-lived, with in vivo half-lives that can be as brief as a few minutes. In some cases, a proteolytic pathway targets and destroys a protein cotranslationally, i.e., an emerging polypeptide chain can be degraded while it is still a ribosome-associated peptidyl-tRNA (1, 2). The regulated and processive degradation of intracellular proteins is carried out largely by the ubiquitin (Ub)- proteasome system (Ub system), in conjunction with molecular chaperones, autophagy, and lysosomal proteolysis. Other mediators of intracellular protein degradation include proteases such as caspases, calpains, and separases. These and other nonprocessive proteases can function as "upstream" components of the Ub system, generating protein fragments that are targeted and degraded to short peptides by Ub-mediated pathways. Proteins that are damaged, misfolded, or otherwise abnormal are often recognized as such and selectively destroyed by the Ub system. Physiologically important exceptions include conformationally perturbed proteins and/or their aggregates that are harmful but cannot be efficaciously repaired or removed. The resulting proteotoxicity underlies both aging and specific diseases, including neurodegeneration.

Additional Information

© 2012 Annual Reviews. Volume publication date July 2012. I am grateful to Christopher Brower, Roger Kornberg, Anna Shemorry, and Brandon Wadas for their helpful comments on the manuscript. Studies in our laboratory are supported by grants from the National Institutes of Health and the March of Dimes Foundation. The author is not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.

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