谷氨酸化酶TTLL5/7介导BAP1谷氨酸化修饰调控造血干细胞自我更新的分子机制研究

Study on mechanism of hematopoiesis is a subject in the frontiers of medical field. Discovering the mechanism of hematopoietic stem cell (HSC) self-renewal will provide theoretical basis on stem cell research and relative hematologic disease therapy. HSC self-renewal is dependent on refined regulation of intracellular signalings and extracellular niches. Glutamylation modification is involved in multiple life process, but the regulatory role of glutamylation in HSC self-renewal has not been reported yet. Our preliminary data show that glutamylases Tubulin Tyrosine Ligase Like 5 (TTLL5) and TTLL7 is highly expressed in long term-HSC (LT-HSC). Ttll5 and Ttll7 deficiency causes abnormal hematopoiesis in peripheral blood, bone marrow and spleen. Ttll5 and Ttll7 deficiency results in increased peripheral white blood cells and BM LT-HSCs. BAP1 was identified as a potential substrate for glutamylation. This study is to further discuss the regulatory role of glutamylation for HSC self-renewal, and to explore the molecular mechanism of glutamylation in promoting HSC self-renewal through BAP1 and its downstream signaling.

造血细胞谱系建立机制的研究是医学领域的前瞻课题，揭示造血干细胞（HSC）自我更新的调控机制，将为干细胞研究和相关血液疾病的治疗提供理论依据。HSC自我更新依赖胞内信号分子和胞外微环境的精细调节。蛋白质的谷氨酸化修饰调控着多种生命活动，但对HSC自我更新的调控作用尚未见报道。申请人的前期工作发现，谷氨酸化酶TTLL5和TTLL7在小鼠骨髓造血干细胞中高表达。Ttll5 KO和Ttll7 KO小鼠外周血、骨髓和脾脏造血异常，外周白细胞数量和骨髓LT-HSC的数量明显增多。我们初步鉴定转录因子BAP1是谷氨酸化酶的可能底物。在此基础上，我们将深入探讨谷氨酸化修饰对HSC自我更新的调控作用，探明谷氨酸化修饰通过调控BAP1及下游信号促进HSC自我更新的分子机制。

造血细胞谱系建立机制的研究是医学领域的前瞻课题，揭示造血干细胞（HSC）自我更新的调控机制，将为干细胞研究和相关血液疾病的治疗提供理论依据。HSC自我更新依赖细胞因子、信号分子、转录因子和胞外微环境的精细调节。IDH2、BAP1等基因对于造血谱系建立是必须的。蛋白质的谷氨酸化修饰调控着多种生命活动。我们的工作发现，谷氨酸化酶TTLL5和TTLL7在小鼠骨髓造血干细胞中高表达。Ttll5 KO和Ttll7 KO小鼠外周血、骨髓和脾脏造血异常，外周白细胞数量和骨髓LT-HSC的数量明显增多。同时负调控蛋白谷氨酸化修饰的胞内羧肽酶CCP3也在造血干细胞中高表达。CCP3基因缺失后导致造血干细胞数量减少及功能受抑，不能自我更新维持。CCP3和TTLL5/7可逆调节了BAP1蛋白在Glu561位点的谷氨酸化修饰。BAP1的谷氨酸化促进其泛素化降解，从而干扰了BAP1下游的转录因子HOXA1的转录，并继而影响LT-HSC的自我更新。我们的结果证明了BAP1的谷氨酸化修饰对HSC的自我更新是必须的。

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