Department of Immunology, University of Washington, Seattle, Washington, USA.
Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington, USA.
J Leukoc Biol. 2021 Nov;110(5):829-837. doi: 10.1002/JLB.2HI0720-463RR. Epub 2021 Jun 1.
Triggering receptor expressed on myeloid cells 2 (TREM2) is an immunoglobulin-like receptor expressed by certain myeloid cells, such as macrophages, dendritic cells, osteoclasts, and microglia. In the brain, TREM2 plays an important role in the immune function of microglia, and its dysfunction is linked to various neurodegenerative conditions in humans. Ablation of TREM2 or its adaptor protein TYROBP causes polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (also known as Nasu-Hakola disorder) with early onset of dementia, whereas some missense variants in TREM2 are associated with an increased risk of late-onset Alzheimer's disease. The human TREM2 gene is subject to alternative splicing, and its major, full-length canonic transcript encompasses 5 exons. Herein, we report a novel alternatively spliced TREM2 isoform without exon 2 (Δe2), which constitutes a sizable fraction of TREM2 transcripts and has highly variable inter-individual expression in the human brain (average frequency 10%; range 3.7-35%). The protein encoded by Δe2 lacks a V-set immunoglobulin domain from its extracellular part but retains its transmembrane and cytoplasmic domains. We demonstrated Δe2 protein expression in TREM2-positive THP-1 cells, in which the expression of full-length transcript was precluded by CRISPR/Cas9 disruption of the exon 2 coding frame. Similar to the full-length TREM2, Δe2 is sorted to the plasma membrane and is subject to receptor shedding. In "add-back" experiments, Δe2 TREM2 had diminished capacity to restore phagocytosis of amyloid beta peptide and promote IFN-I response as compared to full-length TREM2. Our findings suggest that changes in the balance of two mutually exclusive TREM2 isoforms may modify the dosage of full-length transcript potentially weakening some TREM2 receptor functions in the human brain.
髓样细胞表达的触发受体 2（TREM2）是一种免疫球蛋白样受体，由某些髓样细胞表达，如巨噬细胞、树突状细胞、破骨细胞和小胶质细胞。在大脑中，TREM2 在小胶质细胞的免疫功能中发挥重要作用，其功能障碍与人类各种神经退行性疾病有关。TREM2 或其衔接蛋白 TYROBP 的缺失会导致多囊脂膜性骨发育不良伴硬化性脑白质病（也称为 Nasu-Hakola 病），伴有早发性痴呆，而 TREM2 中的一些错义变体与晚发性阿尔茨海默病的风险增加有关。人类 TREM2 基因受选择性剪接调控，其主要的全长有义转录本包含 5 个外显子。在此，我们报道了一种新型的 TREM2 剪接异构体，缺失外显子 2（Δe2），它构成了 TREM2 转录本的相当大一部分，在人类大脑中的个体间表达差异很大（平均频率为 10%；范围为 3.7-35%）。Δe2 编码的蛋白从其细胞外部分缺失 V -set 免疫球蛋白结构域，但保留其跨膜和细胞质结构域。我们在 TREM2 阳性的 THP-1 细胞中证实了 Δe2 蛋白的表达，在这些细胞中，通过 CRISPR/Cas9 破坏外显子 2 的编码框，阻止了全长转录本的表达。与全长 TREM2 相似，Δe2 被分选到质膜上，并发生受体脱落。在“添加回补”实验中，与全长 TREM2 相比，Δe2 TREM2 恢复对淀粉样β肽的吞噬作用和促进 IFN-I 反应的能力减弱。我们的研究结果表明，两种相互排斥的 TREM2 异构体之间平衡的改变可能会改变全长转录本的剂量，从而削弱人类大脑中某些 TREM2 受体的功能。
