Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU, Munich, Germany.
Institute for Immunology, Biomedical Center Munich, Ludwig-Maximilians-Universität München, Planegg-Martinsried, 82152, Munich, Germany.
Nat Commun. 2020 Feb 25;11(1):1031. doi: 10.1038/s41467-020-14809-9.
Clathrin-mediated endocytosis (CME) is critical for internalisation of molecules across cell membranes. The FCH domain only 1 (FCHO1) protein is key molecule involved in the early stages of CME formation. The consequences of mutations in FCHO1 in humans were unknown. We identify ten unrelated patients with variable T and B cell lymphopenia, who are homozygous for six distinct mutations in FCHO1. We demonstrate that these mutations either lead to mislocalisation of the protein or prevent its interaction with binding partners. Live-cell imaging of cells expressing mutant variants of FCHO1 provide evidence of impaired formation of clathrin coated pits (CCP). Patient T cells are unresponsive to T cell receptor (TCR) triggering. Internalisation of the TCR receptor is severely perturbed in FCHO1-deficient Jurkat T cells but can be rescued by expression of wild-type FCHO1. Thus, we discovered a previously unrecognised critical role of FCHO1 and CME during T-cell development and function in humans.
网格蛋白介导的内吞作用（CME）对于跨细胞膜的分子内化至关重要。FCH 结构域仅 1（FCHO1）蛋白是参与 CME 形成早期阶段的关键分子。人类 FCHO1 突变的后果尚不清楚。我们鉴定了十个无关的 T 和 B 细胞淋巴细胞减少症患者，他们在 FCHO1 中有六个不同的突变纯合子。我们证明这些突变要么导致蛋白定位错误，要么阻止其与结合伴侣相互作用。表达 FCHO1 突变体的活细胞成像提供了证据表明网格蛋白包被凹陷（CCP）的形成受损。患者 T 细胞对 T 细胞受体（TCR）触发无反应。FCHO1 缺陷型 Jurkat T 细胞中 TCR 受体的内化受到严重干扰，但通过表达野生型 FCHO1 可以挽救。因此，我们发现了 FCHO1 和 CME 在人类 T 细胞发育和功能中的一个以前未被认识的关键作用。
