Glutamylation of deubiquitinase BAP1 controls self-renewal of hematopoietic stem cells and hematopoiesis
Glutamylation of deubiquitinase BAP1 controls self-renewal of hematopoietic stem cells and hematopoiesis
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去泛素酶 BAP1 的谷氨酰化控制造血干细胞的自我更新和造血
DOI：
10.1084/jem.20190974
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发表时间：
--
影响因子：
15.3
通讯作者：
Fan Z.
中科院分区：
文献类型：
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作者：
Xiong Z;Xia P;Zhu X;Geng J;Wang S;Ye B;Qin X;Qu Y;He L;Fan D;Du Y;Tian Y;Fan Z.
所有造血谱系都来源于有限的造血干细胞（HSC）库。虽然HSC自我更新的机制已被广泛研究，但对蛋白质谷氨酰化和去谷氨酰化在造血中的作用知之甚少。在这里，我们表明，羧肽酶CCP 3是最高的表达在骨髓细胞之间的CCP成员。CCP 3缺乏损害HSC自我更新和造血。去泛素化酶BAP 1是HSC中CCP 3的底物。BAP 1通过TTLL 5和TTLL 7在Glu 651处被谷氨酰化，并且BAP 1-E651 A突变消除BAP 1谷氨酰化。BAP 1谷氨酰化加速其泛素化，从而引发其降解。CCP 3可以去除BAP 1的谷氨酰化，提高其稳定性，从而增强Hoxa 1的表达，导致HSC自我更新，Bap 1 E651 Amice产生更多的LT-HSC和外周血细胞。此外，TTLL 5和TTLL 7缺陷维持BAP 1稳定性以促进HSC自我更新和造血。因此，BAP 1的谷氨酰化和去谷氨酰化调节HSC自我更新和造血。
All hematopoietic lineages are derived from a limited pool of hematopoietic stem cells (HSCs). Although the mechanisms underlying HSC self-renewal have been extensively studied, little is known about the role of protein glutamylation and deglutamylation in hematopoiesis. Here, we show that carboxypeptidase CCP3 is most highly expressed in BM cells among CCP members. CCP3 deficiency impairs HSC self-renewal and hematopoiesis. Deubiquitinase BAP1 is a substrate for CCP3 in HSCs. BAP1 is glutamylated at Glu651 by TTLL5 and TTLL7, and BAP1-E651A mutation abrogates BAP1 glutamylation. BAP1 glutamylation accelerates its ubiquitination to trigger its degradation. CCP3 can remove glutamylation of BAP1 to promote its stability, which enhancesHoxa1expression, leading to HSC self-renewal.Bap1E651Amice produce higher numbers of LT-HSCs and peripheral blood cells. Moreover, TTLL5 and TTLL7 deficiencies sustain BAP1 stability to promote HSC self-renewal and hematopoiesis. Therefore, glutamylation and deglutamylation of BAP1 modulate HSC self-renewal and hematopoiesis.