Ye Buqing, Li Chong, Yang Zhao, Wang Yanying, Hao Junfeng, Wang Li, Li Yi, Du Ying, Hao Lu, Liu Benyu, Wang Shuo, Xia Pengyan, Huang Guanling, Sun Lei, Tian Yong, Fan Zusen
Key Laboratory of Infection and Immunity of CAS, Center for Laboratory Animal Research, Center for Biological Imaging, Key Laboratory of RNA Biology and Beijing Noncoding RNA Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Key Laboratory of Infection and Immunity of CAS, Center for Laboratory Animal Research, Center for Biological Imaging, Key Laboratory of RNA Biology and Beijing Noncoding RNA Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China University of Chinese Academy of Sciences, Beijing 100049, China.
J Exp Med. 2014 Nov 17;211(12):2439-54. doi: 10.1084/jem.20141123. Epub 2014 Oct 20.
Bone marrow progenitor cells develop into mature megakaryocytes (MKs) to produce platelets for hemostasis and other physiological functions. However, the molecular mechanisms underlying megakaryopoiesis are not completely defined. We show that cytosolic carboxypeptidase (CCP) 6 deficiency in mice causes enlarged spleens and increased platelet counts with underdeveloped MKs and dysfunctional platelets. The prominent phenotypes of CCP6 deficiency are different from those of CCP1-deficient mice. We found that CCP6 and tubulin tyrosine ligase-like family (TTLL) members TTLL4 and TTLL6 are highly expressed in MKs. We identify Mad2 (mitotic arrest deficient 2) as a novel substrate for CCP6 and not CCP1. Mad2 can be polyglutamylated by TTLL4 and TTLL6 to modulate the maturation of MKs. CCP6 deficiency causes hyperglutamylation of Mad2 to promote activation of Aurora B, leading to suppression of MK maturation. We reveal that Mad2 polyglutamylation plays a critical role in the regulation of megakaryopoiesis.
骨髓祖细胞发育成成熟的巨核细胞（MKs），以产生用于止血和其他生理功能的血小板。然而，巨核细胞生成的分子机制尚未完全明确。我们发现，小鼠胞质羧肽酶（CCP）6缺乏会导致脾脏肿大、血小板计数增加，同时伴有发育不全的巨核细胞和功能失调的血小板。CCP6缺乏的显著表型与CCP1缺乏的小鼠不同。我们发现CCP6与微管蛋白酪氨酸连接酶样家族（TTLL）成员TTLL4和TTLL6在巨核细胞中高表达。我们确定Mad2（有丝分裂阻滞缺陷2）是CCP6而非CCP1的新底物。Mad2可被TTLL4和TTLL6多聚谷氨酰化，以调节巨核细胞的成熟。CCP6缺乏会导致Mad2过度谷氨酰化，从而促进极光激酶B的激活，导致巨核细胞成熟受到抑制。我们揭示Mad2多聚谷氨酰化在巨核细胞生成的调控中起关键作用。
