The E3 ubiquitin ligase SPOP controls resolution of systemic inflammation by triggering MYD88 degradation
The E3 ubiquitin ligase SPOP controls resolution of systemic inflammation by triggering MYD88 degradation
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DOI：
10.1038/s41590-019-0454-6
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发表时间：
2019-09-01
影响因子：
30.5
通讯作者：
Aifantis, Iannis
中科院分区：
文献类型：
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作者：
Guillamot, Maria;Ouazia, Dahmane;Aifantis, Iannis
对全身感染和损伤的反应需要造血干细胞（HSC）的快速适应，HSC 会增殖并将其分化转向骨髓谱系。人们对了解触发紧急造血计划的信号产生了浓厚的兴趣。然而，HSC 的这种反应对于恢复体内平衡至关重要，但阻止这种反应的机制仍然未知。在这里，我们揭示了E3泛素连接酶斑点型BTB-POZ蛋白（SPOP）抑制HSC的炎症激活。在缺乏 Spop 的情况下，全身炎症以未解决的方式进行，HSC 的持续反应导致致命的表型，让人想起高炎症综合征或脓毒症。我们的蛋白质组学研究揭示，SPOP 通过泛素化先天信号转导器骨髓分化初级反应蛋白 88 (MYD88) 来限制炎症。这些发现揭示了 HSC 内在的翻译后机制，该机制对于紧急造血后重建稳态至关重要。
The response to systemic infection and injury requires the rapid adaptation of hematopoietic stem cells (HSCs), which proliferate and divert their differentiation toward the myeloid lineage. Significant interest has emerged in understanding the signals that trigger the emergency hematopoietic program. However, the mechanisms that halt this response of HSCs, which is critical to restore homeostasis, remain unknown. Here we reveal that the E3 ubiquitin ligase Speckle-type BTB-POZ protein (SPOP) restrains the inflammatory activation of HSCs. In the absence of Spop, systemic inflammation proceeded in an unresolved manner, and the sustained response in the HSCs resulted in a lethal phenotype reminiscent of hyper-inflammatory syndrome or sepsis. Our proteomic studies decipher that SPOP restricted inflammation by ubiquitinating the innate signal transducer myeloid differentiation primary response protein 88 (MYD88). These findings unearth an HSC-intrinsic post-translational mechanism that is essential for reestablishing homeostasis after emergency hematopoiesis.