SUMO-Specific Protease 1 Is Critical for Myeloid-Derived Suppressor Cell Development and Function
SUMO-Specific Protease 1 Is Critical for Myeloid-Derived Suppressor Cell Development and Function
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SUMO 特异性蛋白酶 1 对于骨髓源性抑制细胞的发育和功能至关重要。
DOI：
10.1158/0008-5472.can-18-3497
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发表时间：
2019-08-01
期刊：
影响因子：
11.2
通讯作者：
Cheng, Jinke
中科院分区：
文献类型：
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作者：
Huang, Xian;Zuo, Yong;Cheng, Jinke
骨髓源性抑制细胞（MDSC）可抑制免疫功能并促进肿瘤发生，其丰度与不良预后相关。在这项研究中，我们发现SUMO 1/sentrin特异性肽酶1（SENP 1）调节MDSC的发育和功能。骨髓细胞中的SENP 1缺陷促进MDSC在骨髓、脾和其他器官中的扩增。Senp 1-/- MDSC比Senp 1 +/+ MDSC表现出更强的免疫抑制活性;我们在Senp 1-/-小鼠中观察到骨髓前体细胞的分化没有缺陷。从机制上讲，SENP 1介导的MDSC调节依赖于STAT 3信号传导。我们鉴定了CD 45作为MDSC中的特异性STAT 3磷酸酶。CD 45在MDSC中被SUMO化，SENP 1可以使SUMO化的CD 45去缀合。在Senp 1-/- MDSC中，CD 45高度SUMO化，这降低了其磷酸酶活性，导致STAT 3介导的MDSC发育和功能。这些结果揭示了SENP 1在通过CD 45-STAT 3信号传导轴调节MDSC扩增和功能中的抑制功能。
Myeloid-derived suppressor cells (MDSC) can suppress immunity and promote tumorigenesis, and their abundance is associated with poor prognosis. In this study, we show that SUMO1/sentrin specific peptidase 1 (SENP1) regulates the development and function of MDSC. SENP1 deficiency in myeloid cells promoted MDSC expansion in bone marrow, spleen, and other organs. Senp1-/- MDSC showed stronger immune-suppressive activity than Senp1+/+ MDSC ; we observed no defects in the differentiation of myeloid precursor cell in Senp1-/- mice. Mechanistically, SENP1-mediated regulation of MDSC was dependent on STAT3 signaling. We identified CD45 as a specific STAT3 phosphatase in MDSC. CD45 was SUMOylated in MDSC and SENP1 could de-conjugate SUMOylated CD45. In Senp1-/- MDSC, CD45 was highly SUMOylated, which reduced its phosphatase activity towardSTAT3, leading to STAT3-mediated MDSC development and function. These results reveal a suppressive function of SENP1 in modulating MDSC expansion and function via CD45-STAT3 signaling axis.