Psmc6, the proteasome 26S subunit ATPase 6, is a crucial component of the 26S proteasome, an ATP-dependent proteolytic nanomachine in the ubiquitin-proteasome system (UPS) [5]. The UPS is essential for eliminating abnormal proteins, thus playing a vital role in maintaining proteostasis and influencing various cellular functions and biological processes [5].

In a pSS mouse model, knockdown of Psmc6 reduced lymphocytic infiltration in salivary and lacrimal glands, decreased related inflammatory factors, and increased the proportion of Treg cells, indicating that Psmc6 may promote pSS by inducing immune cell infiltration and inflammatory responses [1]. In an ovariectomy-induced osteoporosis mouse model, Psmc6 gene knockout elevated bone mineral density and the phosphorylation level of PI3K protein, and increased the protein level of cleaved caspase-3/-9. In vitro, Psmc6 inhibition promoted cell cycle progression and cell proliferation, while its overexpression promoted apoptosis and inhibited cell cycle progression and cell proliferation, suggesting that Psmc6 aggravates osteoporosis by inhibiting the PI3K/AKT signal transduction pathway and promoting osteoblast apoptosis [2]. In lung adenocarcinoma cell lines, silencing Psmc6 by siRNAs significantly inhibited cell growth, migration, and invasion. Gene set enrichment analysis showed that Psmc6 overexpression may activate the WNT signaling pathway via degrading the AXIN protein, promoting tumor progression [3]. In ovarian carcinoma cell lines, Psmc6 knockdown reduced cell growth and clonogenicity, especially in cisplatin-resistant cells, and increased sensitivity to cisplatin, indicating a link between Psmc6 and ovarian carcinoma aggressiveness [4].

In conclusion, Psmc6 is involved in multiple biological processes and disease conditions. Studies using gene knockout or knockdown models in mice and cell lines have revealed its roles in promoting primary Sjögren's syndrome, ovariectomy-induced osteoporosis, lung adenocarcinoma, and ovarian carcinoma. These findings provide potential therapeutic targets for treating these diseases.

References:

1. Piao, Yongzhu, Qi, Yutong, Zhang, Hao, Zhong, Xiayuan, Liu, Qingnan. 2023. PSMC6 induces immune cell infiltration and inflammatory response to aggravate primary Sjögren's syndrome. In Journal of human genetics, 68, 263-271. doi:10.1038/s10038-022-01107-z. https://pubmed.ncbi.nlm.nih.gov/36599955/

2. Zhang, Ying, Cao, Xiangyang, Li, Peifeng, Li, Wuyin, Liu, Youwen. 2020. PSMC6 promotes osteoblast apoptosis through inhibiting PI3K/AKT signaling pathway activation in ovariectomy-induced osteoporosis mouse model. In Journal of cellular physiology, 235, 5511-5524. doi:10.1002/jcp.29261. https://pubmed.ncbi.nlm.nih.gov/32017075/

3. Zhang, Jian-Yu, Shi, Ke-Zhi, Liao, Xiang-Yu, Qian, Ying, Li, Dao-Jun. 2021. The Silence of PSMC6 Inhibits Cell Growth and Metastasis in Lung Adenocarcinoma. In BioMed research international, 2021, 9922185. doi:10.1155/2021/9922185. https://pubmed.ncbi.nlm.nih.gov/34239933/

4. Costantino, Matteo, Mirra, Luca, D'arcy, Padraig, Beretta, Giovanni L, Perego, Paola. 2025. PSMC6 regulation of ovarian cancer cisplatin resistance unravels a new mode for proteasome targeting. In International journal of biological sciences, 21, 2258-2274. doi:10.7150/ijbs.104612. https://pubmed.ncbi.nlm.nih.gov/40083690/

5. Xiong, Jing, Pang, Xinping, Song, Xianghu, Yang, Lin, Pang, Chaoyang. 2024. The coherence between PSMC6 and α-ring in the 26S proteasome is associated with Alzheimer's disease. In Frontiers in molecular neuroscience, 16, 1330853. doi:10.3389/fnmol.2023.1330853. https://pubmed.ncbi.nlm.nih.gov/38357597/