Mitotic SENP3 activation couples with cGAS signaling in tumor cells to stimulate anti-tumor immunity.
Mitotic SENP3 activation couples with cGAS signaling in tumor cells to stimulate anti-tumor immunity.
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有丝分裂 SENP3 激活与肿瘤细胞中的 cGAS 信号传导相结合，刺激抗肿瘤免疫
DOI：
10.1038/s41419-022-05063-6
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发表时间：
2022-07-22
影响因子：
9
通讯作者：
Cheng, Jinke
中科院分区：
文献类型：
--
作者：
Hu, Gaolei;Chen, Yalan;Yang, Xinyu;Wang, Yang;He, Jianli;Wang, Tianshi;Fan, Qiuju;Deng, Liufu;Tu, Jun;Tan, Hongsheng;Cheng, Jinke
我们的前期研究表明，SUMO特异性蛋白酶3（SENP 3）的有丝分裂磷酸化可以抑制其在细胞周期G2/M期的去SUMO化活性。SENP 3的抑制在有丝分裂中姐妹染色单体的正确分离中起关键作用。有丝分裂SENP 3磷酸化突变导致染色体不稳定并促进肿瘤发生。在本研究中，我们发现肿瘤细胞中有丝分裂SENP 3磷酸化的突变可以抑制免疫活性小鼠模型中的肿瘤生长。我们进一步检测到肿瘤中CD 8 +T细胞浸润的增加，这对于免疫活性小鼠模型中的抗肿瘤作用是必需的。此外，我们发现有丝分裂SENP 3激活增加微核形成，这可以激活cGAS信号依赖性先天免疫应答。我们证实cGAS信号传导介导有丝分裂SENP 3激活诱导的抗肿瘤免疫。我们进一步表明，p53对DNA损伤的反应通过抑制磷酸化激活有丝分裂SENP 3，并进一步增加细胞衰老以及肿瘤细胞中相关的先天免疫反应。此外，TCGA数据库表明SENP 3表达与先天免疫应答的诱导以及p53突变胰腺癌患者的存活正相关。总之，这些数据揭示了肿瘤细胞中的有丝分裂SENP 3活化可以通过与cGAS信号传导偶联来促进宿主抗肿瘤免疫应答。
Our previous studies show that the mitotic phosphorylation of SUMO-specific protease 3 (SENP3) can inhibit its de-SUMOylation activity in G2/M phase of the cell cycle. Inhibition of SENP3 plays a critical role in the correct separation of sister chromatids in mitosis. The mutation of mitotic SENP3 phosphorylation causes chromosome instability and promotes tumorigenesis. In this study, we find that the mutation of mitotic SENP3 phosphorylation in tumor cells can suppress tumor growth in immune-competent mouse model. We further detect an increase of CD8+T cell infiltration in the tumors, which is essential for the anti-tumor effect in immune-competent mouse model. Moreover, we find that mitotic SENP3 activation increases micronuclei formation, which can activate cGAS signaling-dependent innate immune response. We confirmed that cGAS signaling mediates the mitotic SENP3 activation-induced anti-tumor immunity. We further show that p53 responding to DNA damage activates mitotic SENP3 by inhibiting phosphorylation, and further increases cellular senescence as well as the related innate immune response in tumor cells. Furthermore, TCGA database demonstrates that the SENP3 expression positively correlates with the induction of innate immune response as well as the survival of the p53 mutant pancreatic cancer patients. Together, these data reveal that mitotic SENP3 activation in tumor cells can promote host anti-tumor immune response by coupling with cGAS signaling.
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DOI：
10.1084/jem.20101159
发表时间：
2011-09-26
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fuertes MB;Kacha AK;Kline J;Woo SR;Kranz DM;Murphy KM;Gajewski TF
通讯作者：
Gajewski TF
影响因子：
64.8
作者：
Burrell RA;McClelland SE;Endesfelder D;Groth P;Weller MC;Shaikh N;Domingo E;Kanu N;Dewhurst SM;Gronroos E;Chew SK;Rowan AJ;Schenk A;Sheffer M;Howell M;Kschischo M;Behrens A;Helleday T;Bartek J;Tomlinson IP;Swanton C
通讯作者：
Swanton C
染色体不稳定性通过胞质DNA反应驱动转移。
影响因子：
64.8
作者：
Bakhoum SF;Ngo B;Laughney AM;Cavallo JA;Murphy CJ;Ly P;Shah P;Sriram RK;Watkins TBK;Taunk NK;Duran M;Pauli C;Shaw C;Chadalavada K;Rajasekhar VK;Genovese G;Venkatesan S;Birkbak NJ;McGranahan N;Lundquist M;LaPlant Q;Healey JH;Elemento O;Chung CH;Lee NY;Imielenski M;Nanjangud G;Pe'er D;Cleveland DW;Powell SN;Lammerding J;Swanton C;Cantley LC
通讯作者：
Cantley LC
影响因子：
3.3
作者：
Klein, Ulf R.;Haindl, Markus;Muller, Stefan
通讯作者：
Muller, Stefan
影响因子：
56.9
作者：
Bunz, F;Dutriaux, A;Vogelstein, B
通讯作者：
Vogelstein, B