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Yazgili, A.S.;  Ebstein, F.;  Meiners, S. The Proteasome Activator PA200/PSME4. Encyclopedia. Available online: https://encyclopedia.pub/entry/26825 (accessed on 01 July 2024).
Yazgili AS,  Ebstein F,  Meiners S. The Proteasome Activator PA200/PSME4. Encyclopedia. Available at: https://encyclopedia.pub/entry/26825. Accessed July 01, 2024.
Yazgili, Ayse Seda, Frédéric Ebstein, Silke Meiners. "The Proteasome Activator PA200/PSME4" Encyclopedia, https://encyclopedia.pub/entry/26825 (accessed July 01, 2024).
Yazgili, A.S.,  Ebstein, F., & Meiners, S. (2022, September 02). The Proteasome Activator PA200/PSME4. In Encyclopedia. https://encyclopedia.pub/entry/26825
Yazgili, Ayse Seda, et al. "The Proteasome Activator PA200/PSME4." Encyclopedia. Web. 02 September, 2022.
The Proteasome Activator PA200/PSME4
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This entry is adapted from the peer-reviewed paper 10.3390/biom12081150

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. 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. 

PA200 PSME4 proteasome

1. Expression and Regulation of PA200

PA200/PSME4 contains a putative nuclear localization signal that indicates its nuclear localization [1]. The cross-linking experiments, using cytoplasmic, microsomal, and nuclear extracts, detected PA200 in all three subcellular fractions [2]. Its subcellular localization may thus vary depending on the cell type and cellular function. Several studies observed the colocalization of PA200 with genomic DNA [3][4]. The CHIP seq analysis of the SH-SY5Y neuroblastoma cells found PA200 to be associated with the transcription start site of multiple gene promoters [5].
According to the consensus dataset of the human protein atlas (HPA), the RNA expression of PA200 is highest in the tongue, skeletal muscle, and testes [6]. In contrast, the expression in immune cells is generally low. On the protein level, the data are less reliable. The antibodies used for cell or tissue staining or Western blot analyses are of limited specificity, as suggested by the HPA validation assays [6]. Indeed, Welk et al. recently discovered that the leading commercially available antibody used in most of the studies is unspecific in Western blot and immunohistochemistry analysis. They dissected the specificity of the commercially available anti-PA200 antibodies, using either PA200 gene silencing in human cells or testis tissue from PA200 knockout (KO) mice [7]. In accordance with Welk’s data, the latest entry from the ensemble database denotes only two protein isoforms for the human PA200/PSME4, i.e., the full-length protein and a short version of the 571 amino acids predicted to undergo nonsense-mediated decay [8].
Not much is known about the transcriptional regulation of PA200 expression. The data from Sha et al. reported the transcriptional induction of PSME4 as part of an autoregulatory feedback loop upon proteasome inhibitor treatment [9][10]. This was confirmed by Welk et al., 2016, demonstrating that PSME4 was upregulated two-fold within 24 h after the inhibition of the proteasome with bortezomib, or upon impaired 26S proteasome assembly after the silencing of the 19S subunit Rpn6 [11]. The in silico analysis of the PSME4 promotor confirmed the presence of a highly conserved Nrf1-binding site close to the PSME4 transcriptional start site [11]. Researchers also demonstrated the transcriptional activation of PA200 in response to transforming growth factor beta (TGF-β) [7]. The same study showed the downregulation of PA200 upon the differentiation of the basal stem cells into differentiated airway epithelial cells. Regarding the post-transcriptional regulation of PA200, a single study reported the binding of the microRNA-29b at the 3′ UTR of PA200 [12], but confirmatory data are missing. On the proteasome complex level, the assembly of PA200 into the 20S or 26S proteasome complexes occurs rapidly, as demonstrated in response to acute proteasome inhibition. These data suggest the existence of free PA200 that can be rapidly recruited to the 20S and 26S proteasome to form singly or doubly-capped PA200/20S or hybrid PA200/26S complexes [11]. PA200 was also previously reported to form PA200-20S-19S proteasome complexes upon irradiation in HeLa cells [13]. A recent BioRxiv research also captured the structures of PA200-20S-PA28, as well as the PA200-20S-19S complexes [14]. The cross-linking proteomics analysis from the lab of Marie-Pierre Bousquet confirmed the presence of PA200 as part of the 20S, but also of the 26S complexes. According to their cross-linking data, PA200 locates in the cytoplasm and the nucleus at a similar ratio [2]. It makes up under 5% of the entire proteasome fraction in the cell [15]. A new BioRxiv manuscript by the Merbl lab indicated that PA200 could also bind to 20S complexes containing immunoproteasome subunits [16]. The researchers suggest that the binding of PA200 to the immunoproteasome might counter-regulate the immunoproteasome-specific activities involved in the MHC class I antigenic peptide generation.

2. Structure

The first PA200/20S structure was revealed in 2005, with PA200 isolated from the bovine testes [17]. Three different particles were identified with 23Å resolution: 20S alone; 20S-singly capped with PA200; and 20S-doubly capped with PA200 at a ratio of 50:40:10. PA200 was described as an asymmetric, hollow, dome-like structure bound to all the outer alpha subunits of the 20S (except α7) as a monomer, thereby opening the 20S gate. A recent structure of human PA200 was released in late 2019 in combination with fully in vitro reconstituted human 20S [18]. All α and β subunits of the 20S were expressed using a baculovirus expression system together with five proteasome assembly chaperones that facilitated the in vitro assembly of the 20S. A third baculovirus was used to co-express the human PA200. The high-resolution cryo-EM analysis of this recombinant PA200/20S complex showed a similar dome-like structured PA200 as before, that forms by helical repeats and binds to the α-subunits of the 20S proteasome. The interaction of PA200 with the alpha subunits was resolved in high detail: PA200 bound to 20S via two anchor points: one close to the α5-α6 interface and the other at the α1-α2 interface. Upon the binding of PA200, α5-α7 relocated to the inner surface of the PA200 dome, whereas α3 relocated to have a wider α ring-opening upon PA200 binding. These changes in the α-subunits resulted in allosteric effects on the catalytically active β-subunits, with the β2 active site widening, while the β1 and β5 sites narrowed. Following these structural changes of the catalytic centers, the binding of PA200 to the recombinantly expressed 20S resulted in increased trypsin-like (T-L) (β2) and decreased chymotrypsin-like (CT-L) (β5) and caspase-like (C-L) activities (β1) in vitro. The latest cryo-EM structure of the PA200 (3.75 Å) and PA200-20S (2.72 Å) complex was released in 2020 [19]. The recombinantly expressed human PA200 was complexed with commercially available 20S standard proteasomes and yielded a heterogeneous mix of doubly- or singly capped PA200/20S complexes. The 20S α-subunits were similarly re-arranged upon PA200 binding, as described by Toste-Rego, while no rearrangement was observed on the unbound alpha rings. While the researchers did not specify allosteric changes related to the catalytically active beta sites, their in vitro activity assay revealed the activation of the CT-L activity by approximately 3–4-fold. However, the other activities of the proteasome were not tested. In both structures, PA200 sits directly on the α-rings of 20S, closing the direct access to the 20S but partially opening the 20S entrance pore.
The high resolution of the PA200/20S complexes revealed two positively charged grooves on the exterior of PA200 that formed potential substrate entry sites. However, these channels were obstructed by two negatively charged densities: 5,6[PP]2-InsP4 ((5,6)-bisdiphosphoinositol tetrakisphosphate); and InsP6 (Inositol hexakisphosphate). The substrate entry via PA200 might thus be fine-tuned by these highly negatively charged small signaling molecules. In the previous structures, InsP6 was involved in the structure stabilization, ternary interactions, and folding [20][21]. InsP6 was also reported to play a role in the RNA editing [20], mRNA transcription [22], RNA export [23], and DNA repair [24][25] and the regulation of the histone deacetylases (HDAC) activity [26]. InsP6 also acts as a glue by bringing Cullin-RING ligase (CRL) and COP9 signalosome (CSN) together, and plays a role in UV radiation resistance [27]. This regulatory function of InsP6 on multiple nuclear pathways accords with its high concentration in the nucleus [28]. Not much is known about the function of InsP4. Unfortunately, there is currently no PA200 structure without the presence of these molecules. Therefore, one can only surmise on their functions. Considering that PA200 is also located in the nucleus, InsP6 might interact with PA200 and fine-tune its function, potentially acting as an inhibitor. The above structural data thus provide insights that the PA200 binding might: (1) block large and positively charged substrates from entering; (2) increase selectivity towards the negatively charged substrates; and (3) potentially increase the catalytic activity for the ubiquitinylated substrates in hybrid complexes with 26S.

3. Function

The above-mentioned structural data provide evidence for an opening of the 20S alpha subunit gate and the rearrangement of the proteolytic sites upon the binding of PA200 to the 20S, which facilitates the proteolytic processing of the peptide substrates [18]. Which of the active sites are activated by PA200, however, is controversial. The early biochemical evidence, using PA200 and 20S isolated from bovine testes [1], indicated that PA200 activates the peptide hydrolysis of all of the 20S active sites, but predominantly the C-L activity. The group of Naveen Bangia also reported elevated C-L activity related to the PA200 expression in cells [13]. In stark contrast, the structural data summarized by Rêgo et al. demonstrate the activation of the T-L active site in an in vitro reconstituted PA200/20S complex but the reduction of the C-L and CT-L activities [18]. Guan et al., however, reported three–four-fold activation of the CT-L activity using recombinant human PA200 and human 20S isolated from red blood cells [19]. A recent BioRxiv study reported the activation of the C-L and inhibition of the T-L activities in an in vitro assay using cell extracts and supplemented recombinant human PA200 [16]. To further add to the confusion, a recent research reported an increased activity for all of the catalytic subunits of the 20S when the recombinant human PA200 was added [29]. As the opening of the PA200 dome is small, the entry of the substrates via the PA200 gate would only be allowed for unstructured protein chains or peptides. Even more intriguing, the entry channels into the PA200 appear to be obstructed by highly negatively charged inositol phosphates [18][19]. The difference in the data raises the critical question of which of the substrates are degraded by the complexes containing one or two of the PA200 complexes attached to the 20S core. Moreover, what is the function of PA200 in a 26S hybrid proteasome complex containing the 20S bound to PA200 on one side and the 19S regulator on the other? In that case, the protein substrates would then most probably enter via the 19S regulator into the 20S core for degradation [30]. Does PA200 then act as a "flusher, aiding exit of peptide products through a widened orifice", as suggested by Michael Glickman, and similar to the PA28 proteasome activator family [31]?
One of the few concordant observations on the PA200 function relates to its role in sperm cell differentiation. Khor et al. found that the ubiquitous genetic depletion of PA200 in mice causes male infertility [32]. This observation was confirmed in an independent PA200 KO model [3]. Due to the predominant expression of PA200 in testes, it was suggested that PA200 preferentially associates with the spermatoproteasome, a specialized type of proteasome in which a gamete-specific α4s subunit replaces the α4 isoform of the constitutive proteasomes. This hypothesis was tested in the Bousquet lab: PA200 was enriched two-fold in the spermatoproteasomes (s20S) compared to the constitutive proteasome (c20S) when co-immunoprecipitated with an α4s antibody from bovine testes. However, the s20S and c20S levels were comparable when co-immunoprecipitation was completed with the PA200 antibody, suggesting that PA200 does not preferentially associate with one 20S type. The researchers concluded that, although PA200 seemed to have a function in s20S, it does not act as an exclusive activator during the germ-cell differentiation, as 19S binds more to α4s [29].
The PA200 binding to 20S was found to be increased at least 10-fold in the spermatids (SPTs) and Sertoli (SER) cells compared to spermatogonia (SPG), suggesting a specialized function for PA200 in these cells [29]. A function for PA200 in the acetylation-associated degradation of core histones in response to the DNA double-strand breaks was proposed by Qian et al. [3]. In their study, the testes of PA200 KO mice showed prominent defects in the removal of core histones at the early stage of elongated spermatids [3]. In the pulldown assays, the researchers observed the in vitro binding of acetylated histones to the recombinantly expressed bromodomains from mouse PA200 and its yeast homolog Blm10. The acetylated histones were also degraded in vitro in the presence of bovine PA200 by 20S proteasomes. In accordance with this notion, Mandemaker et al. observed elevated levels of histones upon the silencing of PA200 in the UV-exposed HeLa cells [33]. Another recent research also proposed that PA200 regulates the stability of the histone marking (H3K4me3 and H3K56ac) in aging and transcription [34]. These results are intriguing, but hampered by the recent cryo-EM structures of human recombinant PA200, which did not confirm the presence of a bromodomain in PA200. Moreover, the two positively charged PA200 entry pores might not favor the binding of acetylated histones due to the predominance of positively charged histidine residues [3][18][19]. A very recent study showed that PA200 degrades acetylated-YAP1 in the in the nucleus of mesenchymal stem cells (MSC) in response to the histone deacetylase (HDAC) inhibitor apicidin [35]. The researchers also injected PA200 KO MSCs into an infarcted heart to define the role of PA200 in myocardial infarction. Their results showed that, to maintain the therapeutic function of MSCs in myocardial infarction, the acute degradation of YAP1 in the nucleus by PA200 is necessary. The study by Douida et al. also suggested that the function of PA200 is probably not restricted to acetylated histone degradation [5]. They observed the binding of PA200 to genomic DNA that only partially overlapped with the presence of H3K27ac marks in a ChIP-seq analysis of a neuroblastoma cell line. Accordingly, other studies have implicated PA200 in DNA damage repair [4][13], mitochondrial stress responses [5], responses to proteasome inhibition [11], the glutamine sensitivity of cancer cells [36], myofibroblast differentiation [7], and, potentially, in the dampening of the MHC class I antigen presentation in lung cancer [16]. Most of these studies used the acute silencing of PA200 to investigate the potential functional effects of PA200 depletion in different cell types. As also discussed below in detail, the silencing of PA200 is generally well tolerated by the cells at baseline, but appears to be critical in response to stress. The knockdown of PA200 reduced the survival of cancer cells upon exposure to ionizing radiation and was associated with increased genomic instability and increased sensitivity towards glutamine depletion [4][13][36]. However, the embryonic stem cells isolated from PA200 knockout mice showed no increased sensitivity upon genotoxic stress (radiation of bleomycin), or altered mortality when crossed to p53-deficient mice [32]. In several rat models, the downregulation of PA200 in the endothelial cells by miRNA-29b was associated with increased oxidative stress and endothelial dysfunction [37]. This effect was, however, not unambiguously ascribed to the regulation of PA200, but might be due to additional and/or alternative targets of miRNA-29b. The stable silencing of PA200 in the neuroblastoma cells resulted in a metabolic shift from oxidative phosphorylation to glycolysis and elevated levels of intracellular ROS [38]. The regulation of mitochondrial function by PA200 was also supported by the ChIP-seq data of the same neuroblastoma cell line that demonstrated the binding of PA200 to the promotors of genes involved in cell-cycle progression and apoptosis in response to mitochondrial stress [5].

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Subjects: Biology; Cell Biology; Biochemistry & Molecular Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Ayse Seda Yazgili
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Frédéric Ebstein
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Silke Meiners
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Update Date: 09 Sep 2022
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