Proteolytic Shedding of Human Colony‐Stimulating Factor 1 Receptor and its implication
| Autor: | Yue Shu, Yue Wei, Huaxi Xu, Ziwei Wang, Menghui Ma, Banglian Hu, Honghua Zheng, Shengshun Duan, Yuhang Zhou, Yun-wu Zhang, Sheng Lin, Baoying Cheng, Xiaohua Huang, Xin Li |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
proteolytic shedding Short Communication CSF1R I794T variant Colony stimulating factor 1 receptor 03 medical and health sciences 0302 clinical medicine Western blot Leukoencephalopathies medicine Disintegrin TREM2 Humans Receptors Immunologic Receptor Membrane Glycoproteins medicine.diagnostic_test biology HEK 293 cells Cell Biology CSF1R Cell biology 030104 developmental biology HEK293 Cells Ectodomain Receptors Granulocyte-Macrophage Colony-Stimulating Factor 030220 oncology & carcinogenesis Mutation Proteolysis biology.protein Molecular Medicine Mutant Proteins Amyloid Precursor Protein Secretases Batimastat |
| Zdroj: | Journal of Cellular and Molecular Medicine |
| ISSN: | 1582-4934 1582-1838 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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