Attenuated inflammatory response is a property of embryonic stem cells (ESCs). However, the underlying mechanisms are unclear. Moreover, whether the attenuated inflammatory status is involved in ESC differentiation is also unknown. Here, we found that autophagy-related protein ATG5 is essential for both attenuated inflammatory response and differentiation of mouse ESCs and that attenuation of inflammatory signaling is required for mouse ESC differentiation. Mechanistically, ATG5 recruits FBXW7 to promote ubiquitination and proteasome-mediated degradation of β-TrCP1, resulting in the inhibition of nuclear factor κB (NF-κB) signaling and inflammatory response. Moreover, differentiation defects observed in ATG5-depleted mouse ESCs are due to β-TrCP1 accumulation and hyperactivation of NF-κB signaling, as loss of β-TrCP1 and inhibition of NF-κB signaling rescued the differentiation defects. Therefore, this study reveals a previously uncharacterized mechanism maintaining the attenuated inflammatory response in mouse ESCs and further expands the understanding of the biological roles of ATG5.

减弱炎症反应是胚胎干细胞（ESC）的一个特性。然而，其根本机制尚不清楚。此外，炎症减弱状态是否参与ESC分化也尚不清楚。在这里，我们发现自噬相关蛋白 ATG5 对于减弱炎症反应和小鼠 ESC 的分化至关重要，并且炎症信号的减弱是小鼠 ESC 分化所必需的。从机制上讲，ATG5 招募 FBXW7 促进 β-TrCP1 泛素化和蛋白酶体介导的降解，从而抑制核因子 κB (NF-κB) 信号传导和炎症反应。此外，在 ATG5 耗尽的小鼠 ESC 中观察到的分化缺陷是由于 β-TrCP1 积累和 NF-κB 信号传导过度激活所致，因为 β-TrCP1 的丢失和 NF-κB 信号传导的抑制挽救了分化缺陷。因此，这项研究揭示了一种先前未表征的维持小鼠ESC中炎症反应减弱的机制，并进一步扩展了对ATG5生物学作用的理解。