The life cycle of the 26S proteasome: from birth, through regulation and function, and onto its death

Abstract

The 26S proteasome is a large, ∼2.5 MDa, multi-catalytic ATP-dependent protease complex that serves as the degrading arm of the ubiquitin system, which is the major pathway for regulated degradation of cytosolic, nuclear and membrane proteins in all eukaryotic organisms.

Figure 1

The life cycle of the proteasome. The “birth” of the proteasome is controlled by transcriptional regulation of its different subunits. The biogenesis is organized by transcription factors such as Nrf1 and Rpn4, which are sensitive to changing physiological conditions. The different subunits assemble in a coordinated manner to form the mature proteasome. The 26S proteasome recognizes ubiquitin conjugated substrates in a process mediated by intrinsic and extrinsic ubiquitin receptors. The recognition is regulated by different post-translational modifi cations, disassembly, conformational changes, and cellular localization that the proteasome undergoes. The “death” of the proteasome is at least partially mediated by the lysosome/vacuole/autophagy and cleavage by caspase(s). In the middle is the energy-dependent ubiquitin-substrate conjugate formation catalyzed by E1, E2, and E3.