PAC1‐PAC2 proteasome assembly chaperone retains the core &agr;4–&agr;7 assembly intermediates in the cytoplasm

The 26S proteasome is a large ATP‐dependent protease complex responsible for targeted intracellular degradation of ubiquitin‐tagged proteins and plays essential roles in various cellular processes (Tanaka, 2009). It is composed of a 20S catalytic core particle (CP) and one or two 19S regulatory particles. In eukaryotes, the CP is comprised of stacks of two outer α‐rings and two inner β‐rings. The α‐ring and β‐ring are comprised of seven α‐subunits, α1–α7, and seven β‐subunits, β1–β7, of which β1, β2, and β5 are proteolytically active. Two abutting β‐rings form a proteolytic chamber, whereas α‐rings serve as a gate for substrate entry into the chamber. The efficient assembly of the mammalian 20S CP is orchestrated by dedicated assembly chaperones called proteasome assembly chaperone (PAC) 1–4 and ubiquitin‐mediated proteolysis 1 (UMP1, also called proteasome maturation protein; POMP), which are conserved in yeast (Murata, Yashiroda, & Tanaka, 2009; Ramos & Dohmen, 2008; Ramos, Hockendorff, Johnson, Varshavsky, & Dohmen, 1998). PAC1–PAC2 heterodimer is associated with the α‐ring before β‐subunit incorporation and prevents from forming α‐ring dimers that are off‐pathway products (Hirano et al., 2005). PAC3–PAC4 heterodimer seems to contribute to the α‐ring formation, as knockdown of PAC3 reduces the α‐ring (Hirano et al., 2006; Le Tallec et al., 2007). β2 is the first subunit assembled on the α‐ring, which is dependent on concurrent recruitment of UMP1 (Hirano et al., 2008). The remaining β‐subunits subsequently assemble on the α‐ring in a defined order, during which PAC3–PAC4 dissociates, resulting in formation of a half‐CP. Two half‐CPs dimerize to form a mature CP, which Received: 31 May 2018 | Revised: 19 July 2018 | Accepted: 19 July 2018 DOI: 10.1111/gtc.12631