Mechanisms for Intracellular Protein Degradation

Cells degrade their constituent proteins by multiple mechanisms. Two major degradative systems in eukaryotic cells are lysosomal autophagy and the ubiquitin-proteasome system. Autophagy is a process in which cellular components are engulfed by an intracellular membrane and then delivered to the lysosome for degradation by lysosomal proteases.

Although the general features of autophagy have been known for over 50 years, only recent progress has begun to decipher the molecular mechanisms by which it occurs. Autophagy plays many roles in normal and abnormal biology and is an important response to certain stress conditions. The ubiquitin-proteasome system is the other major pathway for intracellular protein degradation.

This system selectively targets proteins for degradation by covalent modification with a chain of ubiquitin proteins. The polyubiquitin chain is specifically recognized by a large protease complex, the 26S proteasome, which degrades the ubiquitin-modified protein. The ubiquitin-proteasome system accounts for most of the protein degradation that occurs in eukaryotic cells but is highly selective for specific proteins under given cellular conditions.

The molecular and cellular basis for selective protein degradation by the ubiquitin-proteasome system is one of the major achievements of modern biology. The 2004 Nobel Prize in Chemistry was awarded for foundational discovery of the ubiquitin-proteasome system for protein degradation. Study of basic proteasome enzymology and cell biology also led to the development of proteasome inhibitors, some of which have been advanced into drugs (e.g. bortezomib) now used to treat certain forms of cancer.