SUMO and PIAS repress NF-κB activation in a basal chordate
SUMO and PIAS repress NF-κB activation in a basal chordate
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DOI：
10.1016/j.fsi.2023.108754
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发表时间：
2023-04-26
影响因子：
4.7
通讯作者：
Huang，Shengfeng
中科院分区：
文献类型：
--
作者：
Chen，Shenghui;Fu，Xianan;Huang，Shengfeng
小泛素样修饰物（SUMO）调节多种生物学过程，包括MyD 88/TICAMs-IRAKs-TRAF 6-NF-κB通路，其是核心免疫通路之一。然而，它的功能在无脊椎动物和脊椎动物之间是不一致的，并且很少在较低的脊索动物中进行研究，包括文昌鱼和鱼类。在这里，我们研究了SUMO化基因系统的文昌鱼，生活的基础脊索动物。我们发现文昌鱼有一个SUMO化系统，该系统具有一套完整的基因，并保留了几个祖先的特征。我们继续使用哺乳动物细胞系研究它们的分子功能。文昌鱼SUMO 1和SUMO 2均能与NF-κB Rel结合，并以剂量依赖性方式抑制NF-κB活化50-75%。SUMO 2的抑制作用可以通过添加SUMO E2连接酶UBC 9进一步增强。相比之下，虽然人SUMO 2抑制RelA，但人SUMO 1轻微激活RelA。与人PIAS 1 -4类似，文昌鱼皮亚斯也可以作为SUMO E3连接酶，促进其自身SUMO化。这表明文昌鱼皮亚斯在人类细胞中是功能相容的。此外，我们发现文昌鱼皮亚斯不仅能够抑制由MyD 88、TICAM样、TRAF 6和IRAK 4诱导的NF-κB活化，而且能够在SUMO 1/2存在下以剂量不敏感的方式完全抑制NF-κB Rel。这表明皮亚斯可以通过促进Rel SUMO化而有效地阻断Rel。相比之下，在人类中，仅PIAS 3而非PIAS 1/2/4被报道促进NF-κB SUMO化。总之，文昌鱼的发现，以及哺乳动物和其他物种的发现，不仅提供了对动物SUMO系统功能波动性的见解，而且还揭示了它从文昌鱼到鱼类，最终到人类的进化过渡。
Small ubiquitin-like modifier (SUMO) regulates various biological processes, including the MyD88/TICAMs-IRAKs-TRAF6-NF-κB pathway, one of the core immune pathways. However, its functions are inconsistent between invertebrates and vertebrates and have rarely been investigated in lower chordates, including amphioxus and fishes. Here, we investigated the SUMOylation gene system in the amphioxus, a living basal chordate. We found that amphioxus has a SUMOylation system that has a complete set of genes and preserves several ancestral traits. We proceeded to study their molecular functions using the mammal cell lines. Both amphioxus SUMO1 and SUMO2 were shown to be able to attach to NF-κB Rel and to inhibit NF-κB activation by 50–75% in a dose-dependent fashion. The inhibition by SUMO2 could be further enhanced by the addition of the SUMO E2 ligase UBC9. In comparison, while human SUMO2 inhibited RelA, human SUMO1 slightly activated RelA. We also showed that, similar to human PIAS1-4, amphioxus PIAS could serve as a SUMO E3 ligase and promote its self-SUMOylation. This suggests that amphioxus PIAS is functionally compatible in human cells. Moreover, we showed that amphioxus PIAS is not only able to inhibit NF-κB activation induced by MyD88, TICAM-like, TRAF6 and IRAK4 but also able to suppress NF-κB Rel completely in the presence of SUMO1/2 in a dose-insensitive manner. This suggests that PIAS could effectively block Rel by promoting Rel SUMOylation. In comparison, in humans, only PIAS3, but not PIAS1/2/4, has been reported to promote NF-κB SUMOylation. Taken together, the findings from amphioxus, together with those from mammals and other species, not only offer insights into the functional volatility of the animal SUMO system, but also shed light on its evolutionary transitions from amphioxus to fish, and ultimately to humans.