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Ubiquitin-mediated protein degradation.

1988; Elsevier BV; Volume: 263; Issue: 30 Linguagem: Inglês

10.1016/s0021-9258(19)37575-1

1083-351X

Avram Hershko,

Autophagy in Disease and Therapy

A large part of cellular proteins are in a dynamic state of turnover. Protein breakdown is responsible for essential cellular functions such as the modulation of the levels of key enzymes and regulatory proteins and removal of abnormal proteins that arise by biosynthetic errors or postsynthetic damages. The proc- ess is highly selective: the half-lives of individual proteins vary from several minutes to many days (1,2). The biochemical mechanisms of intracellular protein break- down remained obscure for a long time. An unusual mechanism was suggested by observations that it has an absolute requirement for cellular energy (3, 4). Significant progress in the elucidation of the mechanisms of energy-dependent protein breakdown has begun only in the last decade. Available information indicates diversity of mechanisms for protein degradation. The degree of functioning of the various pathways may depend upon specific cell types and changingphysiological situations. Under conditions of nutritional or hormonal deprivation, lysosomal autophagy is greatly accelerated. Lysosomal protein breakdown appears to be largely nonselective, although it has been suggested that certain proteins are targeted to the lysosome by specific amino acid sequences (5). Among cytosolic pathways of protein breakdown, some proteins may be degraded by ATP-dependent proteases such as those described in bacteria (6, 7). Another major system for selective protein degradation is the ubiquitin pathway, in which proteins are committed to degradation by their ligation to ubiquitin, a highly conserved 76-amino acid polypeptide. The objective of this Minireview is to summarize briefly what we have learned and to point out what we yet have to learn about the mode of action of the ubiquitin-mediated protein breakdown system. For more detailed description of the literature, the reader is referred to several earlier reviews (8-ll), a recent book (12), and symposium (13).