# PSMB9

## Overview
PSMB9 is a gene that encodes the proteasome 20S subunit beta 9, a critical component of the immunoproteasome, which is a specialized form of the proteasome complex involved in protein degradation and immune responses. The protein product, also known as β1i, is a proteolytic subunit that plays a vital role in the generation of peptides for major histocompatibility complex class I antigen presentation, thereby contributing to immune surveillance and cellular proteostasis (Kim2023Immunoproteasomespecific). The immunoproteasome, including the β1i subunit, is particularly important under conditions of immune activation and mitochondrial stress, where it helps degrade oxidized and damaged proteins (Kim2021Protein; Kim2023Immunoproteasomespecific). PSMB9 is also involved in muscle differentiation and has been implicated in various clinical conditions, including autoinflammatory diseases and cancer, highlighting its significance in both normal physiology and disease states (Cui2014Identification; Kanazawa2021Neonatalonset).

## Structure
The PSMB9 gene encodes a subunit of the immunoproteasome, specifically the β1i subunit, which is integral to the 20S proteasome complex. The 20S proteasome is a cylindrical structure composed of four stacked rings, with the outer rings consisting of alpha subunits and the inner rings of beta subunits, including PSMB9 (Nandi1997Intermediates). The primary structure of PSMB9 consists of a sequence of amino acids that form the β1i subunit, which is involved in the proteolytic activity of the immunoproteasome. 

The secondary structure of PSMB9 includes alpha helices and beta sheets, which contribute to its folding and stability within the proteasome complex. The tertiary structure involves the three-dimensional folding of the β1i subunit, allowing it to interact with other subunits within the proteasome. The quaternary structure of the immunoproteasome involves the assembly of the β1i subunit into the larger 20S proteasome complex, where it plays a role in antigen processing and protein degradation (Nandi1997Intermediates).

Post-translational modifications of PSMB9 may include phosphorylation, which can affect its activity and interactions within the proteasome complex. The immunoproteasome, including PSMB9, is known for its role in generating peptides for antigen presentation, particularly under conditions of immune activation (Kim2023Immunoproteasomespecific).

## Function
PSMB9 encodes a subunit of the immunoproteasome, which is a specialized form of the proteasome complex involved in protein degradation. In healthy human cells, PSMB9 plays a crucial role in maintaining cellular proteostasis, particularly under conditions of mitochondrial dysfunction. It is part of the 20S and 26S proteasomes, which are responsible for degrading misfolded or damaged proteins, thereby preventing protein aggregation and maintaining protein homeostasis (Kim2023Immunoproteasomespecific).

PSMB9 is upregulated in response to mitochondrial stress, a process that is dependent on the translation elongation factor EEF1A2. This upregulation enhances proteasome activity, which is essential for the degradation of oxidized proteins and the prevention of proteotoxicity (Kim2021Protein; Kim2023Immunoproteasomespecific). The immunoproteasome, including PSMB9, is known for generating peptides for major histocompatibility complex class I antigen presentation, contributing to immune surveillance (Kim2023Immunoproteasomespecific).

In skeletal muscle cells, PSMB9 is crucial for proper differentiation. Its expression is significantly upregulated during muscle differentiation, and its suppression leads to impaired myotube formation and increased protein oxidation and apoptosis, indicating its role in regulating protein degradation and apoptosis during muscle cell differentiation (Cui2014Identification).

## Clinical Significance
Mutations and alterations in the PSMB9 gene have been linked to various diseases and conditions. A heterozygous missense mutation, specifically the c.467G>A (p.G156D) mutation in PSMB9, has been associated with neonatal-onset autoinflammation and immunodeficiency. This mutation affects the immunoproteasome's β1i subunit, leading to impaired 20S proteasome activity while maintaining normal 26S proteasome function. Patients with this mutation exhibit symptoms such as skin rash, myositis, pulmonary hypertension, and immunodeficiency, which are collectively termed as proteasome-associated autoinflammation and immunodeficiency disease (PRAID) (Kanazawa2021Neonatalonset).

In cancer, PSMB9 expression levels have been implicated in the progression and prognosis of various types. In clear cell renal cell carcinoma (ccRCC), higher mRNA expression levels of PSMB9 are associated with more advanced cancer stages and poorer overall survival (Jiang2022Comprehensive). In urothelial bladder carcinoma, the PSMB9 rs17587 G>A SNP is significantly associated with increased cancer risk, suggesting its potential as a biomarker (Elhawary2023Sequence). Additionally, PSMB9 expression is linked to immune response modulation in the tumor microenvironment, influencing clinical outcomes in cancers such as ovarian cancer and urothelial cancer (Wang2020CD8+; Li2021Integrated).

## Interactions
PSMB9, a subunit of the immunoproteasome, is involved in several protein interactions that are crucial for its function in cellular proteostasis and immune responses. It is part of the 20S and 26S proteasome complexes, which are responsible for protein degradation. PSMB9-containing proteasomes are recruited to mitochondria, where they degrade oxidized and damaged proteins, particularly under conditions of mitochondrial dysfunction (Kim2023Immunoproteasomespecific). This recruitment is facilitated by the interaction of PSMB9 with stress-induced proteins like HSPB1, which helps prevent protein aggregation by promoting proteasomal degradation (Kim2023Immunoproteasomespecific).

PSMB9 also interacts with other proteasome subunits to form the 20S core complex, which is essential for its proteolytic activity. The study by Liu et al. highlights that PSMB9 is involved in a protein-protein interaction network across various subcellular locations, including the cytosol, extracellular space, membrane, and nucleus, indicating its diverse functional roles (Liu2022Immune). These interactions are crucial for the regulation of immune responses and the maintenance of cellular homeostasis, particularly under stress conditions such as mitochondrial dysfunction and in the context of tumor microenvironments (Liu2022Immune; Kim2023Immunoproteasomespecific).


## References


[1. (Elhawary2023Sequence) Nasser A Elhawary, Samar N Ekram, Iman S Abumansour, Zohor A Azher, Imad A AlJahdali, Najiah M Alyamani, Hind M Naffadi, Ikhlas A Sindi, Abdulaziz Baazeem, Anmar M Nassir, and Ahmad H Mufti. Sequence variants in psmb8/psmb9 immunoproteasome genes and risk of urothelial bladder carcinoma. Cureus, March 2023. URL: http://dx.doi.org/10.7759/cureus.36293, doi:10.7759/cureus.36293. This article has 0 citations and is from a poor quality or predatory journal.](https://doi.org/10.7759/cureus.36293)

[2. (Cui2014Identification) Ziyou Cui, Soyun Michelle Hwang, and Aldrin V. Gomes. Identification of the immunoproteasome as a novel regulator of skeletal muscle differentiation. Molecular and Cellular Biology, 34(1):96–109, January 2014. URL: http://dx.doi.org/10.1128/MCB.00622-13, doi:10.1128/mcb.00622-13. This article has 77 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1128/MCB.00622-13)

[3. (Nandi1997Intermediates) D. Nandi. Intermediates in the formation of mouse 20s proteasomes: implications for the assembly of precursor beta subunits. The EMBO Journal, 16(17):5363–5375, September 1997. URL: http://dx.doi.org/10.1093/emboj/16.17.5363, doi:10.1093/emboj/16.17.5363. This article has 149 citations.](https://doi.org/10.1093/emboj/16.17.5363)

[4. (Liu2022Immune) Junzhe Liu, Xinyu Yang, Qiankun Ji, Lufei Yang, Jingying Li, Xiaoyan Long, Minhua Ye, Kai Huang, and Xingen Zhu. Immune characteristics and prognosis analysis of the proteasome 20s subunit beta 9 in lower-grade gliomas. Frontiers in Oncology, July 2022. URL: http://dx.doi.org/10.3389/fonc.2022.875131, doi:10.3389/fonc.2022.875131. This article has 7 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fonc.2022.875131)

[5. (Wang2020CD8+) Yutao Wang, Kexin Yan, Jiaxing Lin, Yang Liu, Jianfeng Wang, Xuejie Li, Xinxin Li, Zhixiong Hua, Zhenhua Zheng, Jianxiu Shi, Siqing Sun, and Jianbin Bi. Cd8+ t cell co-expressed genes correlate with clinical phenotype and microenvironments of urothelial cancer. Frontiers in Oncology, November 2020. URL: http://dx.doi.org/10.3389/fonc.2020.553399, doi:10.3389/fonc.2020.553399. This article has 32 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fonc.2020.553399)

[6. (Li2021Integrated) Na Li and Xianquan Zhan. Integrated genomic analysis of proteasome alterations across 11,057 patients with 33 cancer types: clinically relevant outcomes in framework of 3p medicine. EPMA Journal, 12(4):605–627, September 2021. URL: http://dx.doi.org/10.1007/s13167-021-00256-z, doi:10.1007/s13167-021-00256-z. This article has 7 citations.](https://doi.org/10.1007/s13167-021-00256-z)

7. (Kim2021Protein) Protein homeostasis is maintained by proteasomes containing PSMB9 induced by EEF1A2 upon mitochondrial stress. This article has 2 citations.

8. (Jiang2022Comprehensive) Comprehensive Analysis of the Expression and Prognosis for PSMBs in Clear Cell Renal Cell Carcinoma. This article has 0 citations.

9. (Kanazawa2021Neonatalonset) Neonatal-onset autoinflammation and immunodeficiency caused by heterozygous missense mutation of the proteasome subunit β-type 9. This article has 0 citations.

[10. (Kim2023Immunoproteasomespecific) Minji Kim, Remigiusz A. Serwa, Lukasz Samluk, Ida Suppanz, Agata Kodroń, Tomasz M. Stępkowski, Praveenraj Elancheliyan, Biniyam Tsegaye, Silke Oeljeklaus, Michal Wasilewski, Bettina Warscheid, and Agnieszka Chacinska. Immunoproteasome-specific subunit psmb9 induction is required to regulate cellular proteostasis upon mitochondrial dysfunction. Nature Communications, July 2023. URL: http://dx.doi.org/10.1038/s41467-023-39642-8, doi:10.1038/s41467-023-39642-8. This article has 13 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/s41467-023-39642-8)