PMID- 31647545 OWN - NLM STAT- MEDLINE DCOM- 20210208 LR - 20210208 IS - 1759-4685 (Electronic) IS - 1674-2788 (Print) IS - 1759-4685 (Linking) VI - 12 IP - 2 DP - 2020 Feb 20 TI - HLA-B-associated transcript 3 (Bat3) stabilizes and activates p53 in a HAUSP-dependent manner. PG - 99-112 LID - 10.1093/jmcb/mjz102 [doi] AB - The p53 pathway is a highly complex signaling network including several key regulators. HAUSP is a critical component of the p53 pathway acting as a deubiquitinase for both p53 and its key repressor Mdm2. Here, we identified a novel HAUSP-interacting protein, HLA-B-associated transcript 3 (Bat3) and found it to be capable of inducing p53 stabilization and activation via a HAUSP-dependent mechanism, resulting in cell growth inhibition. Surprisingly, the deubiquitylating enzymatic activity of HAUSP was not required for this phenomenon. Co-immunoprecipitation showed that p53 coexisted in a complex with Bat3 and HAUSP in vivo, and HAUSP may serve as a binding mediator to enhance the interaction between p53 and Bat3. Further studies revealed that formation of this three-protein complex interfered with the binding of p53 to its proteasome receptor S5a and promoted the accumulation of p53 in nucleus. Notably, Mdm2 protein abundance is also regulated by Bat3 in the presence of HAUSP. Overexpression of Bat3 and HAUSP increases Mdm2 protein levels without influencing the p53-Mdm2 interaction and Mdm2-mediated p53 ubiquitination, indicating that Bat3-HAUSP-mediated protein stabilization is not specific to p53 and different mechanisms may be involved in Bat3-mediated regulation of p53-Mdm2 pathway. Together, our study unravels a novel mechanism by which p53 is stabilized and activated by HAUSP-mediated interaction with Bat3 and implies that Bat3 might function as a tumor suppressor through the stabilization of p53. CI - (c) The Author(s) (2019). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. FAU - Zhang, Rui AU - Zhang R AD - Department of Basic Veterinary, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China. AD - State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing 100193, China. FAU - Cui, Di AU - Cui D AD - Department of Basic Veterinary, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China. AD - State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing 100193, China. AD - Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, China. FAU - Xue, Teng AU - Xue T AD - Department of Basic Veterinary, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China. AD - State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing 100193, China. FAU - Lang, Yue AU - Lang Y AD - Department of Basic Veterinary, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China. AD - State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing 100193, China. FAU - Zhang, Yunfan AU - Zhang Y AD - Department of Basic Veterinary, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China. AD - State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing 100193, China. FAU - Li, Lianjie AU - Li L AD - Department of Basic Veterinary, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China. AD - State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing 100193, China. FAU - Sun, Haili AU - Sun H AD - Department of Basic Veterinary, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China. AD - State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing 100193, China. FAU - Kuang, Yu AU - Kuang Y AD - Department of Basic Veterinary, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China. FAU - Li, Gebin AU - Li G AD - Department of Clinical Veterinary, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China. FAU - Tang, Jun AU - Tang J AD - Department of Basic Veterinary, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China. AD - State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing 100193, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - J Mol Cell Biol JT - Journal of molecular cell biology JID - 101503669 RN - 0 (BAG6 protein, human) RN - 0 (HLA-B Antigens) RN - 0 (Molecular Chaperones) RN - 0 (TP53 protein, human) RN - 0 (Tumor Suppressor Protein p53) RN - EC 2.3.2.27 (MDM2 protein, human) RN - EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2) RN - EC 3.4.19.12 (USP7 protein, human) RN - EC 3.4.19.12 (Ubiquitin-Specific Peptidase 7) RN - EC 3.4.25.1 (Proteasome Endopeptidase Complex) SB - IM MH - Cell Nucleus/metabolism MH - Cell Proliferation/genetics MH - HCT116 Cells MH - HEK293 Cells MH - HLA-B Antigens/*metabolism MH - Humans MH - Molecular Chaperones/genetics/*metabolism MH - Proteasome Endopeptidase Complex/metabolism MH - Protein Stability MH - Proto-Oncogene Proteins c-mdm2/metabolism MH - RNA Interference MH - Signal Transduction/*genetics MH - Transfection MH - Tumor Suppressor Protein p53/*chemistry/*metabolism MH - Ubiquitin-Specific Peptidase 7/genetics/*metabolism MH - Ubiquitination PMC - PMC7109604 OTO - NOTNLM OT - Bat3 OT - HAUSP OT - S5a OT - p53 stabilization OT - proteasome recognition EDAT- 2019/10/28 06:00 MHDA- 2021/02/09 06:00 PMCR- 2019/10/24 CRDT- 2019/10/25 06:00 PHST- 2019/03/28 00:00 [received] PHST- 2019/07/12 00:00 [revised] PHST- 2019/08/26 00:00 [accepted] PHST- 2019/10/28 06:00 [pubmed] PHST- 2021/02/09 06:00 [medline] PHST- 2019/10/25 06:00 [entrez] PHST- 2019/10/24 00:00 [pmc-release] AID - 5603721 [pii] AID - mjz102 [pii] AID - 10.1093/jmcb/mjz102 [doi] PST - ppublish SO - J Mol Cell Biol. 2020 Feb 20;12(2):99-112. doi: 10.1093/jmcb/mjz102.