Human FCHO1 deficiency reveals role for clathrin-mediated endocytosis in development and function of T cells

Marcin Łyszkiewicz, Natalia Ziętara, Laura Frey, Ulrich Pannicke, Marcel Stern, Yanshan Liu, Yanxin Fan, Jacek Puchałka, Sebastian Hollizeck, Ido Somekh, Meino Rohlfs, Tuğba Yilmaz, Ekrem Ünal, Musa Karakukcu, Türkan Patiroğlu, Christina Kellerer, Ebru Karasu, Karl Walter Sykora, Atar Lev, Amos SimonRaz Somech, Joachim Roesler, Manfred Hoenig, Oliver T. Keppler, Klaus Schwarz, Christoph Klein

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


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.

Original languageEnglish
Article number1031
JournalNature Communications
Issue number1
StatePublished - 25 Feb 2020
Externally publishedYes

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