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 Simon, Raz Somech, Joachim Roesler, Manfred Hoenig, Oliver T. Keppler, Klaus Schwarz and Christoph Klein ()
Additional contact information
Marcin Łyszkiewicz: University Hospital, LMU
Natalia Ziętara: University Hospital, LMU
Laura Frey: University Hospital, LMU
Ulrich Pannicke: University of Ulm
Marcel Stern: Faculty of Medicine, LMU München
Yanshan Liu: University Hospital, LMU
Yanxin Fan: University Hospital, LMU
Jacek Puchałka: University Hospital, LMU
Sebastian Hollizeck: University Hospital, LMU
Ido Somekh: University Hospital, LMU
Meino Rohlfs: University Hospital, LMU
Tuğba Yilmaz: Erciyes University
Ekrem Ünal: Erciyes University
Musa Karakukcu: Erciyes University
Türkan Patiroğlu: Erciyes University
Christina Kellerer: University of Ulm
Ebru Karasu: University of Ulm
Karl-Walter Sykora: Hannover Medical School
Atar Lev: Jeffrey Modell Foundation Center, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine Tel Aviv University
Amos Simon: Jeffrey Modell Foundation Center, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine Tel Aviv University
Raz Somech: Jeffrey Modell Foundation Center, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine Tel Aviv University
Joachim Roesler: Carl Gustav Carus Technical University Dresden
Manfred Hoenig: University Medical Centre Ulm
Oliver T. Keppler: Faculty of Medicine, LMU München
Klaus Schwarz: University of Ulm
Christoph Klein: University Hospital, LMU

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-14809-9

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