Dynamic Remodeling of Cellular Proteomes via the Ubiquitin Proteasome System

Description:    Proteolysis stands as a cornerstone of cellular regulation, with the ubiquitin proteasome system (UPS) being pivotal, accounting for the degradation of up to 80% of cellular proteins. The versatility of the UPS is essential, as it ensures precise protein turnover tailored to the diverse demands of different cellular states, particularly during critical phases such as development and differentiation. This adaptability is achieved through modulation of both the function and localization of its components.

In this presentation, I will highlight our recent discovery of Akirin2, a novel player essential for the nuclear import of proteasomes in mammalian cells. By integrating functional genetics with cryo-electron microscopy (cryo-EM), we have delineated a previously uncharted pathway for proteasome import.

Furthermore, I will discuss our innovative use of time-resolved EM to dissect the mechanism by which the proteasome identifies and processes ubiquitinated substrates. This investigation serendipitously unveiled PITHD1 as an intrinsic inhibitor, which maintains proteasomes in a quiescent state until the initiation of differentiation programs is required.

Our findings not only expand the understanding of the UPS but also illuminate the intricate regulatory networks that govern cellular proteostasis and its impact on cellular fate determination.