# PSMD2

## Overview
PSMD2, or Proteasome 26S Subunit, Non-ATPase, 2, is a gene that encodes the protein proteasome 26S subunit ubiquitin receptor, non-ATPase 2. This protein is a non-ATPase subunit of the 19S regulator base of the 26S proteasome, which is a critical component of the ubiquitin-proteasome system (UPS) responsible for protein degradation. The PSMD2 protein plays a pivotal role in recognizing and binding ubiquitinated substrates, facilitating their delivery to the proteasome for degradation. It is involved in various cellular processes including cell cycle regulation, DNA repair, and signal transduction, primarily through its interaction with other proteins and its involvement in the degradation pathway of key cellular regulators (Li2018PSMD2; Liu2023PSMD2). Dysregulation of PSMD2 has been linked to several diseases, particularly cancers, where it is often overexpressed and associated with poor prognosis (Li2018PSMD2).

## Structure
PSMD2, also known as 26S proteasome regulatory subunit RPN1, is a protein that plays a crucial role in the ubiquitin-proteasome system, particularly in the recognition and processing of ubiquitinated substrates. The protein is composed of 909 amino acids and has a molecular weight of approximately 100 kDa. PSMD2 features a leucine-rich repeat-like domain at its N-terminus, which forms a horseshoe-shaped structure with a β-sheet on the inner side. This domain is involved in interactions with the UBL domains of Rad23 and Dsk2 shuttles, which are essential for substrate unloading onto the proteasomal ATPases (Gadhave2020Unstructured).

The protein also contains several long intrinsically disordered protein regions (IDPRs), which are subject to a variety of post-translational modifications. These modifications include 17 phosphorylation sites, 27 ubiquitylation sites, and 1 acetylation site, predominantly located within the IDPRs. These regions are crucial for recognizing polyubiquitinated proteins on the 19S regulatory particle of the 26S proteasome (Gadhave2020Unstructured).

Additionally, PSMD2 interacts with RACK1 and β-catenin, particularly through its Armadillo-like helical domain, which is vital for the molecular interactions and functional implications in processes such as breast cancer cell stability (Tian2023RACK1). However, detailed information on the primary, secondary, tertiary, or quaternary structure of PSMD2, including specific domains, prominent folds, or splice variant isoforms, is not provided in the available literature.

## Function
PSMD2, or Proteasome 26S Subunit, Non-ATPase, 2, is a crucial component of the 19S regulatory particle of the 26S proteasome within the ubiquitin-proteasome system (UPS). This system is essential for degrading up to 80% of intracellular proteins in eukaryotic cells, playing a vital role in maintaining protein homeostasis by regulating the concentration of specific proteins. PSMD2 is involved in the recognition and binding of ubiquitinated substrates, which are then degraded within the proteasome's catalytic core (Li2018PSMD2; Liu2023PSMD2).

In healthy cells, PSMD2 contributes to various biological functions such as cell growth, cell cycle progression, DNA transcription, damage repair, and signal transduction. The protein is particularly important in the regulation of the cell cycle, where it influences the degradation of cell cycle regulators like p21 and p27. This degradation is crucial for the proper progression from the G1 phase to the S phase of the cell cycle, thereby supporting normal cell division and growth (Li2018PSMD2).

Dysfunction or deregulation of PSMD2 and the UPS can lead to severe diseases, including malignancies, highlighting the importance of this protein in cellular health and disease prevention (Li2018PSMD2).

## Clinical Significance
PSMD2 has been implicated in the progression and prognosis of various cancers, including breast cancer and esophageal squamous cell carcinoma (ESCC). In breast cancer, PSMD2 is significantly overexpressed and associated with poor clinical outcomes such as shorter overall survival, distant metastasis-free survival, and recurrence-free survival. High PSMD2 expression correlates with advanced clinicopathological features like larger tumor size and lymph node metastasis (Li2018PSMD2). The gene's role in cancer progression is partly due to its regulation of proteasomal degradation of cell cycle inhibitors p21 and p27, affecting cell proliferation and cycle progression (Li2018PSMD2).

In ESCC, PSMD2 overexpression is linked to advanced disease stages and poor prognosis. It promotes tumor growth and inhibits autophagy, a process involved in cellular degradation and recycling, thus supporting cancer cell survival and proliferation (Liu2023PSMD2). The interaction of PSMD2 with argininosuccinate synthase 1 (ASS1) in ESCC suggests a complex regulatory mechanism where PSMD2 enhances cancer progression by modulating metabolic pathways and autophagy (Liu2023PSMD2).

These findings highlight the potential of PSMD2 as a biomarker for cancer prognosis and a target for therapeutic intervention, underscoring its clinical significance in oncology.

## Interactions
PSMD2, a component of the 19S regulatory particle of the proteasome, interacts with various proteins, playing a crucial role in protein degradation and cellular regulation. It binds to β-catenin, particularly when β-catenin is phosphorylated and ubiquitinated, which is essential for regulating β-catenin's stability in breast cancer cells (Tian2023RACK1). Additionally, PSMD2 interacts with RACK1, where RACK1 competes with β-catenin for binding to the Armadillo-like helical domain of PSMD2, influencing the stability and degradation of β-catenin (Tian2023RACK1).

PSMD2 also interacts with DNAJA4 and MYH9 in nasopharyngeal carcinoma cells, where DNAJA4 recruits PSMD2 to ubiquitinate MYH9, leading to its degradation (Zhang2023DNAJA4). In the context of autophagy, PSMD2 directly interacts with ATG16, a core autophagosomal protein, which is crucial for the formation of autophagosomes and links autophagy to the ubiquitin-proteasome system (Xiong2018ATG16).

Furthermore, PSMD2 is involved in the degradation of the cell cycle regulators p21 and p27 in breast cancer, interacting with these proteins and mediating their proteasomal degradation, with the cooperation of USP14, a deubiquitinating enzyme (Li2018PSMD2). This interaction highlights the role of PSMD2 in cell cycle regulation and cancer progression.


## References


[1. (Xiong2018ATG16) Qiuhong Xiong, Sarah Fischer, Malte Karow, Rolf Müller, Susanne Meßling, and Ludwig Eichinger. Atg16 mediates the autophagic degradation of the 19s proteasomal subunits psmd1 and psmd2. European Journal of Cell Biology, 97(8):523–532, November 2018. URL: http://dx.doi.org/10.1016/j.ejcb.2018.09.002, doi:10.1016/j.ejcb.2018.09.002. (25 citations) 10.1016/j.ejcb.2018.09.002](https://doi.org/10.1016/j.ejcb.2018.09.002)

[2. (Liu2023PSMD2) Yachen Liu, Meng Wu, Shuxiang Xu, Xiangjie Niu, Weiling Liu, Chuanwang Miao, Ai Lin, Yang Xu, and Lili Yu. Psmd2 contributes to the progression of esophageal squamous cell carcinoma by repressing autophagy. Cell & Bioscience, March 2023. URL: http://dx.doi.org/10.1186/s13578-023-01016-4, doi:10.1186/s13578-023-01016-4. (5 citations) 10.1186/s13578-023-01016-4](https://doi.org/10.1186/s13578-023-01016-4)

[3. (Zhang2023DNAJA4) Qun Zhang, Ping Feng, Xun-Hua Zhu, Shi-Qing Zhou, Ming-Liang Ye, Xiao-Jing Yang, Sha Gong, Sheng-Yan Huang, Xi-Rong Tan, Shi-Wei He, and Ying-Qing Li. Dnaja4 suppresses epithelial-mesenchymal transition and metastasis in nasopharyngeal carcinoma via psmd2-mediated myh9 degradation. Cell Death & Disease, October 2023. URL: http://dx.doi.org/10.1038/s41419-023-06225-w, doi:10.1038/s41419-023-06225-w. (1 citations) 10.1038/s41419-023-06225-w](https://doi.org/10.1038/s41419-023-06225-w)

[4. (Gadhave2020Unstructured) Kundlik Gadhave, Prateek Kumar, Shivani Kapuganti, Vladimir Uversky, and Rajanish Giri. Unstructured biology of proteins from ubiquitin-proteasome system: roles in cancer and neurodegenerative diseases. Biomolecules, 10(5):796, May 2020. URL: http://dx.doi.org/10.3390/biom10050796, doi:10.3390/biom10050796. (21 citations) 10.3390/biom10050796](https://doi.org/10.3390/biom10050796)

[5. (Li2018PSMD2) Yunhai Li, Jing Huang, Beilei Zeng, Dejuan Yang, Jiazheng Sun, Xuedong Yin, Mengqi Lu, Zhu Qiu, Weiyan Peng, Tingxiu Xiang, Hongzhong Li, and Guosheng Ren. Psmd2 regulates breast cancer cell proliferation and cell cycle progression by modulating p21 and p27 proteasomal degradation. Cancer Letters, 430:109–122, August 2018. URL: http://dx.doi.org/10.1016/j.canlet.2018.05.018, doi:10.1016/j.canlet.2018.05.018. (95 citations) 10.1016/j.canlet.2018.05.018](https://doi.org/10.1016/j.canlet.2018.05.018)

[6. (Tian2023RACK1) Ruinan Tian, Jianfei Tian, Xiaoyan Zuo, Sixin Ren, He Zhang, Hui Liu, Zhiyong Wang, Yanfen Cui, Ruifang Niu, and Fei Zhang. Rack1 facilitates breast cancer progression by competitively inhibiting the binding of β-catenin to psmd2 and enhancing the stability of β-catenin. Cell Death & Disease, October 2023. URL: http://dx.doi.org/10.1038/s41419-023-06191-3, doi:10.1038/s41419-023-06191-3. (1 citations) 10.1038/s41419-023-06191-3](https://doi.org/10.1038/s41419-023-06191-3)