A proteasome for all occasions

Abstract

In the ubiquitin-proteasome system, substrates fated for destruction first acquire covalent modification by ubiquitin, and are subsequently destroyed by the proteasome. Traditionally, 26S proteasomes have been seen as largely uniform in their composition and functional capacity. Accordingly, cells can control proteasome abundance via transcriptional pathways that mediate concerted regulation of all known proteasome genes. However, recent evidence suggests that the proteasome is also subject to subunit-specific modes of regulation, which serve to alter proteasome function and may generate ensembles of compositionally distinct proteasomes. These modes of proteasome regulation provide varied means to adapt protein degradation pathways to changing conditions in the cell.

Figure 1. Schematic representation of the 26S proteasome

The canonical 26S proteasome is composed of one core particle and one or two regulatory particles, as indicated. The regulatory particle can be further subdivided into the lid and the base. The base contains 6 ATPases (Rpt1–6), and three non-ATPase subunits. The lid contains six PCI domain-containing proteins (Rpn3, Rpn5–7, Rpn9, and Rpn12), two MPN domain-containing protein (Rpn8 & Rpn11), and one additional protein, Rpn15 (also known as Sem1). Adapted from [5].

Figure 2. Model for distinct cellular pathways mediating the proteasome stress response and the ubiquitin stress response

Proteasome levels are controlled via a negative feedback loop involving the transcription factor Rpn4. Ubiquitin levels are controlled, at least in part, via ubiquitin-dependent transcriptional regulation of Ubp6, which increases proteasomal efficiency in ubiquitin regeneration. Adapted from [54].

Figure 3. Model for dual modes of ubiquitin regeneration by Ubp6

The primary effect of Ubp6 on ubiquitin levels is mediated by the catalytic deubiquitinating activity of Ubp6. However, Ubp6 also appears to directly inhibit the proteasome via non-catalytic functions, and this slowing of total flux through the proteasome might provide a second mechanism for ubiquitin stabilization.