Siglecs that Associate with DAP12
Siglecs that Associate with DAP12
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DOI：
10.1007/978-981-15-1580-4_9
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发表时间：
2020-01-01
期刊：
影响因子：
--
通讯作者：
Angata, Takashi
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文献类型：
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作者：
Angata, Takashi
Siglecs是主要在白细胞上表达的跨膜受体样聚糖识别蛋白家族。大多数Siglecs具有称为基于免疫受体酪氨酸的抑制基序（ITIM）的细胞内序列基序，并与含有Src同源区2结构域的酪氨酸磷酸酶-1（SHP-1）结合，并负调节酪氨酸磷酸化介导的细胞内信号传导事件。另一方面，一些Siglecs在跨膜结构域中具有带正电荷的氨基酸残基，并与12 kDa的DNAX活化蛋白（DAP 12）结合，其进而募集脾酪氨酸激酶（Syk）。这些DAP 12相关的Siglecs发挥不同的功能。例如，Siglec-15在整个脊椎动物进化中是保守的，并且通过调节破骨细胞发育和功能在骨稳态中起作用。人Siglec-14和Siglec-16具有抑制性对应物（分别为Siglec-5和Siglec-11），其在细胞外结构域处与它们显示出极高的序列相似性，但与SHP-1相互作用。这种“配对受体”构型中的DAP 12相关Siglec抵消利用抑制性对应物的病原体。在人类中发现了使DAP 12相关的失活Siglecs的多态性（突变），其中一些似乎与人类宿主对细菌诱导的条件的敏感性或抗性有关。对小鼠Siglec-H的研究揭示了它在调节适应性免疫中发挥的复杂而有趣的功能。许多问题仍未得到解答，对DAP 12相关Siglecs的进一步分子和遗传研究将产生具有翻译相关性的有价值的见解。
Siglecs are a family of transmembrane receptor-like glycan-recognition proteins expressed primarily on leukocytes. Majority of Siglecs have an intracellular sequence motif called immunoreceptor tyrosine-based inhibitory motif (ITIM) and associate with Src homology region 2 domain-containing tyrosine phosphatase-1 (SHP-1), and negatively regulate tyrosine phosphorylation-mediated intracellular signaling events. On the other hand, some Siglecs have a positively charged amino acid residue in the transmembrane domain and associate with DNAX activation protein of 12 kDa (DAP12), which in turn recruits spleen tyrosine kinase (Syk). These DAP12-associated Siglecs play diverse functions. For example, Siglec-15 is conserved throughout vertebrate evolution and plays a role in bone homeostasis by regulating osteoclast development and function. Human Siglec-14 and -16 have inhibitory counterparts (Siglec-5 and -11, respectively), which show extremely high sequence similarity with them at the extracellular domain but interact with SHP-1. The DAP12-associated Siglec in such "paired receptor" configuration counteracts the pathogens that exploit the inhibitory counterpart. Polymorphisms (mutations) that render DAP12-associated inactive Siglecs are found in humans, and some of these appear to be associated with sensitivity or resistance of human hosts to bacterially induced conditions. Studies of mouse Siglec-H have revealed complex and intriguing functions it plays in regulating adaptive immunity. Many questions remain unanswered, and further molecular and genetic studies of DAP12-associated Siglecs will yield valuable insights with translational relevance.