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.

Keywords: PA200; PSME4; proteasome.

Figure 1

Analysis of the specificity of commercially available anti-PA200 antibodies. (A) A time course of transient PA200 silencing in human A549 alveolar epithelial cells was analyzed for specific recognition of PA200 by Western blotting using the leading commercially available anti-PA200 antibody #1 (PA1-1961, Thermo Fisher Scientific, Waltham, MA, USA); (B) Protein lysates of testes were prepared from wild type (WT) and PA200^-/- (KO) mice (obtained from [7]) and analyzed for detection of PA200 by Western blotting using antibody #1; (C) Immunohistochemistry (IHC) staining of paraffin-embedded testis sections from wild type (WT) and PA200^-/- (KO) mice with antibody #1; (D) Samples used in (A) were analyzed with the specific PA200-targeting antibody #2 (NBP1-22236, Novus Biologicals, Littleton, CO, USA); (E) Samples used in (B) were analyzed with the specific PA200-targeting antibody #3 (NBP2-32575, Novus Biologicals, Littleton, USA); (F) Tissue sections from wild type (WT) and PA200^-/- (KO) mice were stained with antibody #4 (sc-135512, Santa Cruz, Dallas, TX, USA) by IHC. Figures show representative results for experiments performed with n = 3. (Reproduced with permission from Welk et al., Scientific Reports; published by Nature Publishing Group, 2019 [5]).

Figure 2

Structure of PA200. (A) Overall view of PA200-20S-PA200 complex structure (PA200 (pink) and 20S (blue) structure PDB ID: 6REY); (B) Top view of PA200 with two negatively charged molecules; (C) 5,6[PP]2-InsP4 ((5,6)-bisdiphosphoinositol tetrakisphosphate; and (D) InsP6 (Inositol hexakisphosphate).

Figure 3

Mutations in the PA200/PSME4 gene. (A) Lollipop mutation diagram, using mutation data from the TCGA PanCancer Atlas Studies. The matching mutation types are reflected in the coloring of the circles on the mutation diagram. The circle’s color is chosen according to the mutation type that occurs most frequently when multiple mutation types occur at the same site. Missense mutations (light green, unknown significance), Truncating mutations (light grey, unknown significance), Inframe mutations (dark brown, unknown significance), Splice mutations (light brown, unknown significance), SV/Fusion mutation (light pink); (B) PA200/PSME4 alteration frequencies in different cancer types as obtained from the TCGA PanCancer Atlas Studies (data and figures retrieved from cBioPortal on the 16th of August, 2022 [41,42,43]).