Proper control of inflammatory responses is essential for embryonic development, but the underlying mechanism is poorly understood. Here, we show that under physiological conditions, inactivation of ISG15, an inflammation amplifier, is associated with the interaction of Beclin 1 (Becn1), via its ECD domain, with STAT3 in the major fetal hematopoietic organ of mice. Conditional loss of Becn1 caused sequential dysfunction and exhaustion of fetal liver hematopoietic stem cells, leading to lethal inflammatory cell-biased hematopoiesis in the fetus. Molecularly, the absence of Becn1 resulted in the release of STAT3 from Becn1 tethering and subsequent phosphorylation and translocation to the nucleus, which in turn directly activated the transcription of ISG15 in fetal liver hematopoietic cells, coupled with increased ISGylation and production of inflammatory cytokines, whereas inactivating STAT3 reduced ISG15 transcription and inflammation but improved hematopoiesis potential, and further silencing ISG15 mitigated the above collapse in the Becn1 null hematopoietic lineage. The Becn1-STAT3-ISG15 axis remains functional in autophagy-disrupted fetal hematopoietic organs. These results suggest that Becn1, in an autophagy-independent manner, secures hematopoiesis and survival of the fetus by directly inhibiting STAT3-ISG15 activation to prevent cytokine storms. Our findings highlight a previously undocumented role of Becn1 in governing ISG15 to safeguard the fetus.

中文翻译：

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Beclin 1 阻止 ISG15 介导的细胞因子风暴，以确保胎儿造血和存活。


适当控制炎症反应对于胚胎发育至关重要，但对其潜在机制知之甚少。在这里，我们表明在生理条件下，炎症放大器 ISG15 的失活与 Beclin 1 （Becn1） 通过其 ECD 结构域与小鼠主要胎儿造血器官中的 STAT3 相互作用有关。Becn1 的条件性缺失导致胎儿肝脏造血干细胞的连续功能障碍和耗竭，导致胎儿发生致命的炎性细胞偏向性造血。在分子上，Becn1 的缺失导致 STAT3 从 Becn1 栓系中释放出来，随后磷酸化和易位到细胞核，这反过来又直接激活了胎儿肝造血细胞中 ISG15 的转录，再加上 ISGylation 和炎性细胞因子的产生增加，而灭活 STAT3 减少了 ISG15 转录和炎症，但提高了造血潜力， 进一步沉默 ISG15 减轻了 Becn1 无效造血谱系中的上述崩溃。Becn1-STAT3-ISG15 轴在自噬破坏的胎儿造血器官中仍然有效。这些结果表明，Becn1 以不依赖自噬的方式通过直接抑制 STAT3-ISG15 激活来防止细胞因子风暴，从而确保胎儿的造血和存活。我们的研究结果强调了 Becn1 在控制 ISG15 以保护胎儿方面以前未被证实的作用。