Proteolytic Shedding of Human Colony-Stimulating Factor 1 Receptor and its implication.
Proteolytic Shedding of Human Colony-Stimulating Factor 1 Receptor and its implication.
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人集落刺激因子1受体的蛋白水解脱落及其意义
DOI：
10.1111/jcmm.16474
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发表时间：
2021-05
影响因子：
5.3
通讯作者：
Zheng H
中科院分区：
文献类型：
--
作者：
Wei Y;Ma M;Lin S;Li X;Shu Y;Wang Z;Zhou Y;Hu B;Cheng B;Duan S;Huang X;Xu H;Zhang YW;Zheng H
集落刺激因子1受体（CSF 1 R）和髓样细胞上表达的触发受体2（TREM 2）都是跨膜受体，主要在脑中由小胶质细胞表达。这两种与神经退行性疾病相关的小胶质细胞表达基因的突变最近被归类为“小胶质细胞病”。一些文献表明，CSF 1 R和TREM 2经历逐步脱落，TREM 2变体损害或加速处理。然而，CSF 1 R变体是否影响CSF 1 R的脱落仍然是未知的。在此，将含有人CSF 1 R或TREM 2的质粒瞬时转染到人胚肾（HEK）293 T细胞中。使用蛋白质印迹和/或ELISA测定，我们证明，与TREM 2相似，CSF 1 R胞外域的N末端片段（NTF）脱落和随后的CSF 1 R膜内C末端片段（CTF）分别由解整合素和金属蛋白酶（ADAM）家族成员和γ分泌酶产生。并且通过用巴马司他（一种ADAM抑制剂）或DAPT或化合物E（一种γ-分泌酶抑制剂）处理来抑制脱落。重要的是，我们表明，切割的片段，细胞外结构域和细胞内结构域的一种常见的疾病相关的I794 T变异体，显着减少。总之，我们的研究证明了人CSF 1 R裂解的逐步方法，并有助于了解CSF 1 R I794 T变体在伴有轴突球体和色素胶质细胞（ALSP）的成人发作性白质脑病中的致病性。这些研究还表明，从CSF 1 R释放的切割的胞外域片段可被提议作为ALSP的诊断生物标志物。
Both Colony‐stimulating factor 1 receptor (CSF1R) and triggering receptor expressed on myeloid cells‐2 (TREM2) are trans‐membrane receptors and are expressed in the brain primarily by microglia. Mutations in these two microglia‐expressed genes associated with neurodegenerative disease have recently been grouped under the term “microgliopathy”. Several literatures have indicated that CSF1R and TREM2 encounters a stepwise shedding and TREM2 variants impair or accelerate the processing. However, whether CSF1R variant affects the shedding of CSF1R remains elusive. Here, plasmids containing human CSF1R or TREM2 were transiently transfected into the human embryonic kidney (HEK) 293T cells. Using Western Blot and/or ELISA assay, we demonstrated that, similar to those of TREM2, an N‐terminal fragment (NTF) shedding of CSF1R ectodomain and a subsequent C‐terminal fragment (CTF) of CSF1R intra‐membrane were generated by a disintegrin and metalloprotease (ADAM) family member and by γ‐secretase, respectively. And the shedding was inhibited by treatment with Batimastat, an ADAM inhibitor, or DAPT or compound E, a γ‐secretase inhibitor. Importantly, we show that the cleaved fragments, both extracellular domain and intracellular domain of a common disease associated I794T variant, were decreased significantly. Together, our studies demonstrate a stepwise approach of human CSF1R cleavage and contribute to understand the pathogenicity of CSF1R I794T variant in adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). These studies also suggest that the cleaved ectodomain fragment released from CSF1R may be proposed as a diagnostic biomarker for ALSP.
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影响因子：
2.9
作者：
Barreda, DR;Hanington, PC;Belosevic, M
通讯作者：
Belosevic, M
可溶性 TREM2 会诱导炎症反应并增强小胶质细胞的存活。
DOI：
10.1084/jem.20160844
发表时间：
2017-03-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Zhong L;Chen XF;Wang T;Wang Z;Liao C;Wang Z;Huang R;Wang D;Li X;Wu L;Jia L;Zheng H;Painter M;Atagi Y;Liu CC;Zhang YW;Fryer JD;Xu H;Bu G
通讯作者：
Bu G
影响因子：
9.8
作者：
Hemming ML;Elias JE;Gygi SP;Selkoe DJ
通讯作者：
Selkoe DJ
影响因子：
4.6
作者：
Pridans, Clare;Sauter, Kristin A.;Baer, Kristin;Kissel, Holger;Hume, David A.
通讯作者：
Hume, David A.
影响因子：
15.9
作者：
Chitu V;Gokhan Ş;Nandi S;Mehler MF;Stanley ER
通讯作者：
Stanley ER