Trim47 prevents hematopoietic stem cell exhaustion during stress by regulating MAVS-mediated innate immune pathway
Fang Chen, Yukai Lu, Yang Xu, Naicheng Chen, Lijing Yang, Xiaoyi Zhong, Hao Zeng, Yanying Liu, Zijin Chen, Qian Zhang, Shilei Chen, Jia Cao, Jinghong Zhao, Song Wang, Mengjia Hu, Junping Wang
Abstract
The maintenance of hematopoietic stem cell (HSC) functional integrity is essential for effective hematopoietic regeneration when suffering from injuries. Studies have shown that the innate immune pathways play crucial roles in the stress response of HSCs, whereas how to precisely modulate these pathways is not well characterized. Here, we identify the E3 ubiquitin ligase tripartite motif-containing 47 (Trim47) as a negative regulator of the mitochondrial antiviral-signaling protein (MAVS)-mediated innate immune pathway in HSCs. We find that Trim47 is predominantly enriched in HSCs, and its deficiency impairs the function and survival of HSCs after exposure to 5-flurouracil (5-FU) and irradiation (IR). Mechanistically, Trim47 impedes the excessive activation of the innate immune signaling and inflammatory response via K48-linked ubiquitination and degradation of MAVS. Collectively, our findings demonstrate a role of Trim47 in preventing stress-induced hematopoietic failure and thus provide a promising avenue for treatment of related diseases in the clinic. During periods of stress, it is required to maintain the haematopoietic stem cell (HSC) pool. Here the authors show that Trim47 is important in the survival and function of HSCs after exposure to stress, and prevents haematopoietic failure by inhibiting MAVS-mediated excessive activation of the innate immune pathway.