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.
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DOI：
10.1038/s41419-020-03299-8
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发表时间：
2021-01-07
影响因子：
9
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Guo S;Chen Y;Yang Y;Zhang X;Ma L;Xue X;Qiao Y;Wang J
在泛素（Ub）蛋白酶体系统（UPS）的稳态调节可能是重要的肝癌的发展。Tribbles同源物2 （TRIB2）已知影响肝癌中的Ub E3连接酶（E3s）。然而，TRIB2是否以其他方式调控UPS及其机制尚不清楚。在这里，我们发现TRIB2主要通过刺激Ub的蛋白酶体降解来降低Ub水平。在蛋白酶体中，蛋白酶体20S亚基β 5 （PSMB5）对TRIB2的功能至关重要，尽管它不直接与TRIB2相互作用。而聚（rC）结合蛋白2 （PCBP2）则直接与TRIB2和PSMB5相互作用。PCBP2是TRIB2诱导PSMB5活性和降低Ub水平的先决条件。肝癌标本中发现TRIB2与PCBP2有显著相关性。有趣的是，TRIB2抑制PCBP2的k48泛素化，从而提高其水平。因此，我们建立了TRIB2协同并刺激PCBP2降低Ub水平的模型。此外，TRIB2和PCBP2诱导的Ub水平降低依赖于k48泛素化。PCBP2可能是TRIB2的下游因子之一，它们的相互作用依赖于TRIB2的DQLVPD元件和PCBP2的KH3结构域。这种相互作用是维持肝癌细胞活力和促进肿瘤生长所必需的。机制上，谷胱甘肽过氧化物酶4作为TRIB2和PCBP2的末端效应物之一，保护肝癌细胞免受氧化损伤。综上所述，这些数据表明，除了影响E3s外，TRIB2还通过调节蛋白酶体中PSMB5的活性来降低Ub通量，从而在调节UPS中发挥关键作用，并且靶向TRIB2可能通过增强治疗剂诱导的氧化损伤而有助于肝癌的治疗。
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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影响因子：
4.6
作者：
Guan H;Shuaib A;Leon DD;Angyal A;Salazar M;Velasco G;Holcombe M;Dower SK;Kiss-Toth E
通讯作者：
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影响因子：
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作者：
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影响因子：
20.3
作者：
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通讯作者：
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