Focus on us,
Get more information about cscb2020
As an important tumor suppressor gene, p53 is precisely regulated in cells. The occurrence and development of most tumors are closely related to the disorder of p53 gene. In the highly complex signal regulatory network of p53 pathway, HAUSP (also known as USP7) is an important ubiquitinase, which can competitively bind with p53 and its ubiquitin ligase MDM2. Through the dynamic removal of p53 and / or MDM2 ubiquitin, HAUSP precisely regulates the protein level in cells, and then plays an important role in tumor occurrence and development [1, 2]. Therefore, HAUSP has become an important target for tumor treatment and drug development [3,4].
Recently, Tang Jun / Zhang Rui team of Agricultural University of China published a report titled "hla-b-associated script 3 (BAT3) stabilizes and activates p53 in a HAUSP dependent" in Journal of Molecular Cell Biology (JMCB) The cover article of "manner" for the first time reveals a new mechanism by which apoptosis related factor BAT3 regulates the stability and activity of p53 through HAUSP (but not dependent on its ubiquitination activity). Paper cover
Speeding p53 on the Highway Interchange
P53 pathway is a highly complex signal network. The balance between MDM2 mediated ubiquitination and HAUSP mediated de ubiquitination is considered to be the key to p53 homeostasis. The cover image "accelerated p53 on the highway overpass" metaphors how p53 is stabilized and activated through the interaction of p53-hausp-bat3 mediated by HAUSP. However, in this complex regulatory network, our vision can only see a corner, and the dynamic regulatory mechanism of p53 still needs to be further explored and improved. This picture was created by Zhang Rui, the first author of the paper and co-author, and drawn by Yang Shuyu, an undergraduate of China Agricultural University.
In this study, a new factor BAT3 interacting with HAUSP was identified by mass spectrometry and protein immunocoprecipitation analysis. Further study showed that overexpression of BAT3 alone did not affect the protein level and activity of p53, but overexpression of BAT3 and HAUSP at the same time significantly enhanced the stability of p53 and the activation of downstream genes (p21 and puma) (compared with overexpression of HAUSP only). The same conclusion was obtained in RNAi knockdown experiment, indicating that BAT3 depends on HAUSP to play its role of stabilizing and activating p53. Interestingly, after mutation of the active site of HAUSP, BAT3 can still interact with HAUSP and play a stable role in p53, suggesting that HAUSP has a regulatory mechanism independent of the activity of ubiquitinase.
BAT3 depends on HAUSP to stabilize and activate p53
If the past ubiquitination pathway is not available, what mechanism does BAT3 and HAUSP use to stabilize p53? Through in-depth study of protein interaction, we found that BAT3 can form a triple complex of bat3-hausp-p53 with HAUSP and p53 in vivo, while HAUSP, as an intermediate medium, enhances the interaction between BAT3 and p53, interferes with the binding of p53 and its proteasome receptor s5a, hinders the degradation of p53 proteasome pathway, promotes its accumulation in the nucleus, and plays an anti-tumor role.
Molecular mechanism of inhibition of p53 degradation by bat3-hausp-p53 trimer
It is worth noting that MDM2, as the E3 ubiquitin ligase of p53 degradation, is also upregulated by BAT3 and HAUSP, but overexpression of BAT3 and HAUSP does not affect the interaction of p53-MDM2 and MDM2 mediated p53 ubiquitination. These results indicate that bat3-hausp-mediated protein stability can also affect other proteins except p53, and the molecular mechanism of its regulation of MDM2 still needs to be further explored. In conclusion, this study is the first to reveal the new mechanism of BAT3 regulating the stability and activity of p53 through HAUSP, and to further explore the role and mechanism of BAT3 on other proteins in p53 signaling pathway, which will help us better understand the dynamic fine regulation of p53 pathway.
reference:
1. Li M, et al. (2002) Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. Nature 416, 648-653.
2. Li M, Brooks CL, Kon N, & Gu W (2004) A dynamic role of HAUSP in the p53-Mdm2 pathway. Mol. Cell. 13, 879-886.
3. Tavana O & Gu W (2017) Modulation of the p53/MDM2 interplay by HAUSP inhibitors. J. Mol. Cell Biol. 9, 45-52.
4. Liu, Y., Tavana, O., and Gu, W. (2019). p53 modifications: exquisite decorations of the powerful guardian. J. Mol. Cell Biol. 11, 564–577.
Author brief introduction
Tang Jun, a distinguished professor of China Agricultural University, graduated from biochemistry major of Lanzhou University with a bachelor's degree. He obtained a doctor's degree in molecular and cell biology from the University of Massachusetts in the United States, and carried out postdoctoral research at the University of Pennsylvania in the United States. Selected candidates of "New Century Excellent Talents" support plan of the Ministry of education. Tang Jun research group is committed to the comparative medical research of human and animal, focusing on the regulatory mechanism of tumor and inflammatory pathway and its role in tumorigenesis and virus infection. The research results were successively published in nature cell biology, genes dev, cell death difference, oncogene, PLoS patterns, JCS, JBC, jvi and other magazines.
Zhang Rui, associate professor (left), China Agricultural University, is the co corresponding author and co first author of the paper;
Cui Yun (right), a doctoral student from China Agricultural University, is the co-author of the paper.
Source: JMCB science frontier
1980-2020