The Proteasome Activator PA200/PSME4: An Emerging New Player in Health and Disease

Abstract

Proteasomes comprise a family of proteasomal complexes essential for maintaining protein homeostasis. Accordingly, proteasomes represent promising therapeutic targets in multiple human diseases. Several proteasome inhibitors are approved for treating hematological cancers. However, their side effects impede their efficacy and broader therapeutic applications. Therefore, understanding the biology of the different proteasome complexes present in the cell is crucial for developing tailor-made inhibitors against specific proteasome complexes. Here, we will discuss the structure, biology, and function of the alternative Proteasome Activator 200 (PA200), also known as PSME4, and summarize the current evidence for its dysregulation in different human diseases. We hereby aim to stimulate research on this enigmatic proteasome regulator that has the potential to serve as a therapeutic target in cancer.

Induction of proteasomal activity in mammalian cells by lifespan-extending tRNA synthetase inhibitors

“…Increased proteasomal capacity has been found to be responsible for some extremely long-lived phenotypes in yeast, worms and flies, indicating that further research exploring this process in mammals is of great interest to the aging field [ 3 , 4 , 8 – 10 , 18 ]. Altogether, the promotion of these two processes to increase protein degradation has been shown to increase health in many models, underscoring the importance of an organism’s ability to maintain protein homeostasis in healthy aging [ 3 , 5 , 40 , 58 – 63 ].…”

Orthogonal approaches required to measure proteasome composition and activity in mammalian brain tissue

“…This core particle is referred to as the 20S proteasome and can be associated with a multisubunit complex that makes up the 19S regulatory cap to form a 26S (one cap, ∼1.5 MDa) or 30S (two caps, ∼2.5 MDa) proteasome ( 5 , 46 , 49 , 50 , 51 ). Proteasomes can also associate with a variety of regulator and activator complexes that can modulate proteasome activity and promote the opening of the 20S proteasome ( 52 , 53 , 54 , 55 ). While the natural behavior of the 19S-capped proteasomes is to mediate ATP-dependent unfolding and degradation of ubiquitylated proteins, the 20S proteasome without the 19S cap does not require ubiquitin or ATP and is thought to be primarily tasked with degrading already unfolded proteins (Note: Unless stated otherwise, when discussing 20S proteasome, we refer to a 20S proteasome without a 19S cap) ( 4 , 7 , 56 ).…”

Proteasome Interactome and Its Role in the Mechanisms of Brain Plasticity

“…Expression of this factor sharply increases in the case of tumorigenic processes and, conversely, is suppressed in neurodegenerative diseases. Currently, this factor attracts much attention as a possible therapeutic target [34].…”