Putting it all together: intrinsic and extrinsic mechanisms governing proteasome biogenesis

Abstract

BACKGROUND:The 26S proteasome is at the heart of the ubiquitin-proteasome system, which is the key cellular pathway for the regulated degradation of proteins and enforcement of protein quality control. The 26S proteasome is an unusually large and complicated protease comprising a 28-subunit core particle (CP) capped by one or two 19-subunit regulatory particles (RP). Multiple activities within the RP process incoming ubiquitinated substrates for eventual degradation by the barrel-shaped CP. The large size and elaborate architecture of the proteasome have made it an exceptional model for understanding mechanistic themes in macromolecular assembly. OBJECTIVE:In the present work, we highlight the most recent mechanistic insights into proteasome assembly, with particular emphasis on intrinsic and extrinsic factors regulating proteasome biogenesis. We also describe new and exciting questions arising about how proteasome assembly is regulated and deregulated in normal and diseased cells. METHODS:A comprehensive literature search using the PubMed search engine was performed, and key findings yielding mechanistic insight into proteasome assembly were included in this review. RESULTS:Key recent studies have revealed that proteasome biogenesis is dependent upon intrinsic features of the subunits themselves as well as extrinsic factors, many of which function as dedicated chaperones. CONCLUSION:Cells rely on a diverse set of mechanistic strategies to ensure the rapid, efficient, and faithful assembly of proteasomes from their cognate subunits. Importantly, physiological as well as pathological changes to proteasome assembly are emerging as exciting paradigms to alter protein degradation in vivo.

Dynamic Regulation of the 26S Proteasome: From Synthesis to Degradation

“…Assembly of the holo-26S proteasome following subunit synthesis is a highly complex process that requires numerous dedicated chaperones and maturation factors (Figure 3; Howell et al, 2017; Rousseau and Bertolotti, 2018). Construction of the CP and the Rpt ring of the RP are particularly challenging as compared to their bacterial and archeal counterparts, due to diversification of the α, β and Rpt subunits.…”

An Allosteric Interaction Network Promotes Conformation State-Dependent Eviction of the Nas6 Assembly Chaperone from Nascent 26S Proteasomes

“…Proteasome assembly is a conserved process that depends upon both intrinsic subunit features and extrinsic assembly chaperones ( Howell et al, 2017 ). The lid, base, and CP can assemble independent of one another, although the base likely can also assemble using the CP as a scaffold ( Kusmierczyk et al, 2008 ; Park et al, 2009 ).…”

“…Much progress has been made toward understanding how base assembly chaperones promote proteasome biogenesis (reviewed in Howell et al, 2017 ). Generally, the four constitutive base chaperones prevent premature docking of proteasomal ATPases onto the surface of the CP by providing a steric blockade of the interaction surface.…”

Proteomic analysis of affinity-purified 26S proteasomes identifies a suite of assembly chaperones in Arabidopsis

“…The complexity and size of 26S proteasomes have made them an excellent model for understanding how intricate macromolecular structures are rapidly and faithfully built from dozens of components. Detailed studies on proteasome assembly in yeast, and then in archaea and mammalian cells, revealed that this process is mediated by a collection of dedicated chaperones that enhance assembly rate and fidelity (13,14). CP assembly begins with construction of the individual ␣-rings, which is accelerated by two heterodimeric chaperones, termed Pba1-Pba2 and Pba3-Pba4 in yeast (15,16).…”