2. Academic Validation
  3. TRIB2 modulates proteasome function to reduce ubiquitin stability and protect liver cancer cells against oxidative stress

TRIB2 modulates proteasome function to reduce ubiquitin stability and protect liver cancer cells against oxidative stress

  • Cell Death Dis. 2021 Jan 7;12(1):42. doi: 10.1038/s41419-020-03299-8.
Susu Guo 1,  Yuxin Chen 2,  Yueyue Yang 1,  Xiao Zhang 3,  Lifang Ma 3,  Xiangfei Xue 1,  Yongxia Qiao 4,  Jiayi Wang 5 6
Affiliations

Affiliations

  • 1 Department of Clinical Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai, 200072, China.
  • 2 West China Second University Hospital, Sichuan University, Sichuan, 610041, China.
  • 3 Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China.
  • 4 School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. yongxia.qiao@shsmu.edu.cn.
  • 5 Department of Clinical Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai, 200072, China. karajan2@163.com.
  • 6 Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China. karajan2@163.com.
PMID: 33414446 DOI: 10.1038/s41419-020-03299-8
Abstract

The regulation of homeostasis in the Ubiquitin (Ub) Proteasome system (UPS) is likely to be important for the development of liver Cancer. Tribbles homolog 2 (TRIB2) is known to affect Ub E3 Ligases (E3s) in liver Cancer. However, whether TRIB2 regulates the UPS in other ways and the relevant mechanisms are still unknown. Here, we reveal that TRIB2 decreased Ub levels largely by stimulating Proteasome degradation of Ub. In the Proteasome, Proteasome 20S subunit beta 5 (PSMB5) was critical for the function of TRIB2, although it did not directly interact with TRIB2. However, poly (rC) binding protein 2 (PCBP2), which was identified by mass spectrometry, directly interacted with both TRIB2 and PSMB5. PCBP2 was a prerequisite for the TRIB2 induction of PSMB5 activity and decreased Ub levels. A significant correlation between TRIB2 and PCBP2 was revealed in liver Cancer specimens. Interestingly, TRIB2 suppressed the K48-ubiquitination of PCBP2 to increase its level. Therefore, a model showing that TRIB2 cooperates and stimulates PCBP2 to reduce Ub levels was established. Additionally, the reduction in Ub levels induced by TRIB2 and PCBP2 was dependent on K48-ubiquitination. PCBP2 was one of the possible downstream factors of TRIB2 and their interaction relied on the DQLVPD element of TRIB2 and the KH3 domain of PCBP2. This interaction was necessary to maintain the viability of the liver Cancer cells and promote tumor growth. Mechanistically, Glutathione Peroxidase 4 functioned as one of the terminal effectors of TRIB2 and PCBP2 to protect liver Cancer cells from oxidative damage. Taken together, the data indicate that, in addition to affecting E3s, TRIB2 plays a critical role in regulating UPS by modulating PSMB5 activity in Proteasome to reduce Ub flux, and that targeting TRIB2 might be helpful in liver Cancer treatments by enhancing the oxidative damage induced by therapeutic agents.

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