ATG5 attenuates inflammatory signaling in embryonic stem cells to control differentiation

Attenuated inflammatory responses to both inflammation-related cytokines and infectious agents are recognized as a unique property of embryonic stem cells (ESCs). Although an increasing number of studies have reported this attenuation, the underlying molecular mechanisms are still unclear. Moreover, whether the attenuated inflammatory status is involved in ESC differentiation is completely unknown. Here, we found that the autophagy-related protein ATG5 is essential for both the attenuated inflammatory response and the differentiation of ESCs, and that the attenuation of inflammatory signaling is required for ESC differentiation. Mechanistically, ATG5 promotes 26S proteasome-mediated degradation of the SCF (SKP1-cullin-1-F-box-protein) E3 ubiquitin ligase β-TrCP1 (beta-transducin repeat containing E3 ubiquitin protein ligase 1), which is a well-known positive regulator of NF-κB signaling and the inflammatory response. Another SCF E3 ubiquitin ligase, FBXW7 (F-box and WD repeat domain containing 7), which is recruited by ATG5, was found to be the E3 ubiquitin ligase responsible for the ubiquitination and degradation of β-TrCP1. Moreover, the differentiation defects observed in ATG5-depleted ESCs are due to the accumulation of β-TrCP1 and the related hyperactivation of NF-κB signaling, as loss of β-TrCP1 and inhibition of NF-κB signaling rescued the differentiation defects in ATG5-depleted ESCs. Therefore, this study reveals a previously uncharacterized mechanism employed by ESCs to maintain the inflammatory response in an attenuated state and further provides novel insight into the biological roles of ATG5, especially in the control of the inflammatory response and differentiation of ESCs.