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

Nat Commun. 2020 Feb 25;11(1):1031. doi: 10.1038/s41467-020-14809-9.

Marcin Łyszkiewicz ^# ¹ ², Natalia Ziętara ^# ³ ⁴, Laura Frey ³, Ulrich Pannicke ⁵, Marcel Stern ⁶, Yanshan Liu ³, Yanxin Fan ³, Jacek Puchałka ³, Sebastian Hollizeck ³, Ido Somekh ³, Meino Rohlfs ³, Tuğba Yilmaz ⁷, Ekrem Ünal ⁷, Musa Karakukcu ⁷, Türkan Patiroğlu ⁷ ⁸, Christina Kellerer ⁵, Ebru Karasu ⁵, Karl-Walter Sykora ⁹, Atar Lev ¹⁰, Amos Simon ¹⁰, Raz Somech ¹⁰, Joachim Roesler ¹¹, Manfred Hoenig ¹², Oliver T Keppler ⁶ ¹³, Klaus Schwarz ⁵ ¹⁴, Christoph Klein ¹⁵

Affiliations

1 Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU, Munich, Germany. [email protected].
2 Institute for Immunology, Biomedical Center Munich, Ludwig-Maximilians-Universität München, Planegg-Martinsried, 82152, Munich, Germany. [email protected].
3 Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU, Munich, Germany.
4 Institute for Immunology, Biomedical Center Munich, Ludwig-Maximilians-Universität München, Planegg-Martinsried, 82152, Munich, Germany.
5 Institute for Transfusion Medicine, University of Ulm, Ulm, Germany.
6 Max von Pettenkofer Institute, Virology, National Reference Center for Retroviruses, Faculty of Medicine, LMU München, Munich, Germany.
7 Department of Pediatrics, Division of Pediatric Hematology & Oncology, Erciyes University, Kayseri, Turkey.
8 Department of Pediatrics, Division of Pediatric Immunology, Erciyes University, Kayseri, Turkey.
9 Department of Pediatric Hematology/Oncology, Hannover Medical School, Hannover, Germany.
10 Pediatric Department A and the Immunology Service, Jeffrey Modell Foundation Center, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine Tel Aviv University, Tel Aviv, Israel.
11 Department of Pediatrics, Carl Gustav Carus Technical University Dresden, Dresden, Germany.
12 Department of Pediatrics, University Medical Centre Ulm, Ulm, Germany.
13 German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany.
14 Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Wuerttemberg, Hessen, Germany.
15 Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU, Munich, Germany. [email protected].
# Contributed equally.

PMID: 32098969 DOI: 10.1038/s41467-020-14809-9

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.

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