The E3 ubiquitin ligase MG53 inhibits hepatocellular carcinoma by targeting RAC1 signaling.
The E3 ubiquitin ligase MG53 inhibits hepatocellular carcinoma by targeting RAC1 signaling.
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DOI：
10.1038/s41389-022-00414-6
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发表时间：
2022-07-20
期刊：
影响因子：
6.2
通讯作者：
Han, Lihui
中科院分区：
文献类型：
--
作者：
Ma, Xiaomin;Ma, Xiaoxiao;Zhu, Lihui;Zhao, Yunxue;Chen, Mengmeng;Li, Tao;Lin, Yueke;Ma, Dapeng;Sun, Caiyu;Han, Lihui
RAS相关的C3肉毒毒素底物1(RAC1)的过度表达和过度激活与包括肝细胞癌在内的多种肿瘤的侵袭性生长和其他恶性特征有关。然而，RAC1在肝细胞癌中表达和激活的调控机制尚不完全清楚。在这里，我们证明了E3泛素连接酶MG53(也称为三方基序72，TRIM72)是RAC1的直接抑制剂，它催化了RAC1的泛素化，并进一步抑制了肝癌细胞中RAC1的活性。在机制上，MG53通过其卷曲的卷曲结构域直接与RAC1结合，并通过催化肝癌细胞中Lys48(K48)连接的RAC1在Lys5残基的多泛素化来抑制RAC1的活性。我们进一步证明，MG53通过抑制RAC1-MAPK信号轴，显著抑制了肝癌细胞的恶性行为，并增强了肝癌细胞对索拉非尼的化疗敏感性。综上所述，我们确定MG53是一种新的RAC1抑制因子和肿瘤抑制因子，它通过诱导RAC1的K48连接的多泛素化，进而抑制RAC1-MAPK信号通路来抑制肝癌的进展。总之，我们的研究通过调控MG53为RAC1过度激活的肿瘤提供了一种新的治疗策略。
Ras-related C3 botulinum toxin substrate 1 (RAC1) overexpressiosn and hyperactivation are correlated with aggressive growth and other malignant characteristics in a wide variety of cancers including hepatocellular carcinoma (HCC). However, the regulatory mechanism of RAC1 expression and activation in HCC is not fully understood. Here, we demonstrated that E3 ubiquitin ligase MG53 (also known as tripartite motif 72, TRIM72) acted as a direct inhibitor of RAC1, and it catalyzed the ubiquitination of RAC1 and further inhibited RAC1 activity in HCC cells. Mechanistically, MG53 directly bound with RAC1 through its coiled-coil domain and suppressed RAC1 activity by catalyzing the Lys48 (K48)-linked polyubiquitination of RAC1 at Lys5 residue in HCC cells. We further demonstrated that MG53 significantly suppressed the malignant behaviors of HCC cells and enhanced the chemosensitivity of HCC cells to sorafenib treatment by inhibiting RAC1-MAPK signaling axis. In summary, we identified MG53 as a novel RAC1 inhibitor and tumor suppressor in HCC, and it suppressed HCC progression by inducing K48-linked polyubiquitination of RAC1 and further inhibiting the RAC1-MAPK signaling. Altogether, our investigation provided a new therapeutic strategy for RAC1 overactivated tumors by modulating MG53.
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影响因子：
--
作者：
Li Q;Ren B;Gui Q;Zhao J;Wu M;Shen M;Li D;Li D;Chen K;Tao M;Liang R
通讯作者：
Liang R
N epsilon-羧甲基-赖氨酸通过 Vav1/Rac1 途径负向调节泡沫细胞迁移
影响因子：
4.1
作者：
Bao, Zhengyang;Zhang, Lili;Wang, Zhongqun
通讯作者：
Wang, Zhongqun
DOI：
10.1073/pnas.1808830116
发表时间：
2019-01-22
影响因子：
11.1
作者：
Marston, Daniel J.;Anderson, Karen L.;Hanein, Dorit
通讯作者：
Hanein, Dorit
影响因子：
11.4
作者：
Navarro-Lerida, Inmaculada;Sanchez-Perales, Sara;Del Pozo, Miguel A.
通讯作者：
Del Pozo, Miguel A.
NOD2通过靶向AMPK通路抑制肿瘤发生并增加肝细胞癌的化疗敏感性。
影响因子：
9
作者：
Ma, Xiaomin;Qiu, Yumin;Han, Lihui
通讯作者：
Han, Lihui