Fine-tuning of thymocyte development by ubiquitination-mediated stability control of the ESCRT protein CHMP5
Fine-tuning of thymocyte development by ubiquitination-mediated stability control of the ESCRT protein CHMP5
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通过泛素化介导的 ESCRT 蛋白 CHMP5 稳定性控制微调胸腺细胞发育
DOI：
10.1038/cmi.2017.91
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
S.
中科院分区：
文献类型：
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作者：
Watanabe;M. and Hatakeyama;S.
T淋巴细胞由骨髓中的造血干细胞产生，在胸腺中成熟并迁移至外周淋巴组织。胸腺由皮质和髓质组成，皮质中有许多未成熟的胸腺细胞，髓质中有更多成熟的胸腺细胞。表达由TCR基因重排产生的T细胞受体（TCR）αβ链的发育中的胸腺细胞仅在通过判断其TCR与皮质胸腺上皮细胞（cTEC）的主要组织相容性复合物（MHC）分子上呈递的肽抗原之间的相互作用强度而确定其为有用细胞时选择性分化。不能识别肽-MHC配体的细胞不能接收存活信号，并且只有能够以适当的亲和力识别肽-MHC配体的细胞增殖并分化成成熟T细胞。这种检查点机制被称为积极选择。另一方面，在对肽-MHC配体表现出强烈反应的细胞中诱导细胞死亡，这一机制被称为负选择。尽管根据TCR和肽-MHC配体之间的亲和力产生不同反应的机制尚不清楚，但有丝分裂原活化蛋白激酶（MAPK）途径以及TCR刺激中下游信号的强度和定位可能参与调节T细胞的选择过程。例如，p38、c-Jun NH 2-末端激酶（JNK）和细胞外信号调节激酶5（ERK 5）是负选择的重要MAPK信号，但不是正选择所必需的。另一方面，ERK 1/2的磷酸化对正选择很重要，但对负选择不重要。还已知磷酸化ERK的定位在正选择和负选择之间不同。负选择刺激诱导磷酸化ERK比正选择刺激更靠近质膜。Adoro等2最近报道，作为一种不依赖于MAPK通路的新机制，足够的TCR输入通过稳定促存活因子之一B细胞淋巴瘤2（Bcl-2）来促进阳性选择的胸腺细胞的存活。
Tlymphocytes are generated from hematopoietic stem cells in bone marrow, mature in the thymus and migrate to peripheral lymphoid tissues. The thymus is composed of the cortex and medulla, and there are many immature thymocytes in the cortex and more mature thymocytes are present in the medulla. Developing thymocytes expressing T-cell receptor (TCR) αβ chains generated by TCR gene rearrangement selectively differentiate only when they are determined to be useful cells by judgement of the strength of interaction between their TCR and peptide antigens presented on major histocompatibility complex (MHC) molecules of cortical thymic epithelial cells (cTECs). Cells unable to recognize peptide-MHC ligands cannot receive survival signals, and only cells that can recognize peptide-MHC ligands with an appropriate affinity proliferate and differentiate into mature T cells. This checkpoint mechanism is called positive selection. On the other hand, cell death is induced in cells that show strong responses to peptide-MHC ligands, a mechanism that is called negative selection. Although the mechanism that produces different responses depending on the affinity between TCR and peptide-MHC ligands has not been unclear, the mitogen-activated protein kinase (MAPK) pathway, and strength and localization of downstream signals in TCR stimulation are likely involved in regulation of the selection process of T cells. 1 For example, p38, c-Jun NH2-terminal kinase (JNK), and extracellular signal-regulated kinase 5 (ERK5) are important MAPK signals for negative selection but are not required for positive selection. On the other hand, phosphorylation of ERK1/2 is important for positive selection but not for negative selection. It is also known that localization of phosphorylated ERK differs between positive selection and negative selection. Stimuli of negative selection induce phosphorylated ERK closer to the plasma membrane than stimuli of positive selection do. As a new mechanism not dependent on the MAPK pathway, Adoro et al. 2 recently reported that an adequate input of TCR promotes the survival of positively selected thymocytes via the stabilization of one of the pro-survival factors, B-cell lymphoma 2 (Bcl-2).