P4hb, also known as prolyl 4-hydroxylase subunit beta, is an endoplasmic reticulum molecular chaperone protein with oxidoreductase, chaperone and isomerase activities. It can catalyze the formation, breakage and rearrangement of disulfide bonds, which is crucial for maintaining the oxidizing environment in the endoplasmic reticulum [3,4,5]. P4hb has been implicated in protein processing in the endoplasmic reticulum, including N -glycan modification and protein metabolic processes responding to ER stress [5].

In an ESCC-induced cachexia mouse model, ESCC-derived extracellular vesicles containing P4HB were found to induce apoptosis of skeletal muscle cells. P4HB promoted apoptotic response through activating the ubiquitin-dependent proteolytic pathway and regulating the stability of phosphoglycerate dehydrogenase (PHGDH) and subsequent anti-apoptotic protein Bcl-2. The P4HB inhibitor, CCF642, rescued apoptosis of muscle cells in vitro and prevented body weight loss and muscle wasting in the mouse model, suggesting P4HB as a potential intervention target for cachexia in ESCC patients [1]. In HepG2 cells, defective P4HB UFMylation promoted P4HB protein degradation via the ubiquitin-proteasome pathway, causing mitochondrial function damage, oxidative stress, and endoplasmic reticulum stress, indicating UFMylation as a key post-translational modification for P4HB stability and function [2].

In conclusion, P4hb plays essential roles in maintaining protein homeostasis in the endoplasmic reticulum and is involved in various cellular processes. Studies using mouse models, such as the ESCC-induced cachexia model, have revealed its significance in disease-related processes like muscle wasting in ESCC-associated cachexia, providing potential therapeutic targets for relevant diseases [1].

References:

1. Gao, Xiaohan, Wang, Yan, Lu, Fang, Song, Yongmei, Zhan, Qimin. 2021. Extracellular vesicles derived from oesophageal cancer containing P4HB promote muscle wasting via regulating PHGDH/Bcl-2/caspase-3 pathway. In Journal of extracellular vesicles, 10, e12060. doi:10.1002/jev2.12060. https://pubmed.ncbi.nlm.nih.gov/33732415/

2. Zhu, Jing, Ma, Xirui, Jing, Yu, Liu, Huifang, Chen, Fengling. 2022. P4HB UFMylation regulates mitochondrial function and oxidative stress. In Free radical biology & medicine, 188, 277-286. doi:10.1016/j.freeradbiomed.2022.06.237. https://pubmed.ncbi.nlm.nih.gov/35753586/

3. Feng, Dechao, Wang, Jie, Li, Dengxiong, Zhang, Chi, Wei, Wuran. 2023. Targeting Prolyl 4-Hydroxylase Subunit Beta (P4HB) in Cancer: New Roads to Travel. In Aging and disease, 15, 2369-2380. doi:10.14336/AD.2023.1126. https://pubmed.ncbi.nlm.nih.gov/38029391/

4. Wang, Feiyang, Yu, Zhixiang, Liu, Xiaohan, Liu, Yan, Zou, Zhenhong. 2023. A meta-analysis and bioinformatics analysis of P4HB expression levels in the prognosis of cancer patients. In Pathology, research and practice, 245, 154474. doi:10.1016/j.prp.2023.154474. https://pubmed.ncbi.nlm.nih.gov/37119730/

5. Wu, Yucai, Peng, Yiji, Guan, Bao, Li, Xuesong, Zhou, Liqun. 2020. P4HB: A novel diagnostic and prognostic biomarker for bladder carcinoma. In Oncology letters, 21, 95. doi:10.3892/ol.2020.12356. https://pubmed.ncbi.nlm.nih.gov/33376528/