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; Christoph Klein

doi:10.1038/s41467-020-14809-9

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

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25 Scopus citations

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.

Original language	English
Article number	1031
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-14809-9
State	Published - 25 Feb 2020
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2020, The Author(s).

Funding

We thank the patients and their families for participating in this research. We would like to thank Alper Özcan, Murat Cansever, Fulya Bektas, Ebru Yilmaz, (Erciyes University, Kayseri, Turkey), Can Acıpayam (Kahramanmaraş Sütçü imam University, Kahra-manmaraş) and all medical personnel for excellent patient care. We thank Andreas Krueger and Ludger Klein for critical review of this manuscript; Emmanuel Boucrot (University College London, UK) and Harvey McMahon (MRC-LMB, Cambridge, UK) for sharing various constructs of wt FCHO proteins. The SK-MEL-2 cell line with RFP-tagged clathrin light chain was kindly provided by David G. Drubin (UC Berkeley, USA). We are grateful to Jan E. Heil, Monica Stich and Alexander Liebstein from ZEISS laboratories for access to their facilities and technical help on microscopy experiments. The studies were supported by the Bundesministerium für Bildung und Forschung (BMBF) (German PID-NET, grants to K.S., M.H., J.R., and C.K.), the DAAD (Rare disorders of the immune system), the Else-Kröner-Fresenius Stiftung, DFG (Gottfried Wilhelm Leibniz programme and SFB914 (to C.K.), German Research Foundation (DFG LY150/1-1) (to M.Ł.), grants KE742/5-1 and KE742/7-1 (to O.T.K.)) and the Care-for-Rare Foundation.

Funders	Funder number
Else-Kröner-Fresenius Stiftung	SFB914
Deutscher Akademischer Austauschdienst
Deutsche Forschungsgemeinschaft	DFG LY150/1-1
Bundesministerium für Bildung und Forschung

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Łyszkiewicz, M., Ziętara, N., Frey, L., Pannicke, U., Stern, M., Liu, Y., Fan, Y., Puchałka, J., Hollizeck, S., Somekh, I., Rohlfs, M., Yilmaz, T., Ünal, E., Karakukcu, M., Patiroğlu, T., Kellerer, C., Karasu, E., Sykora, K. W., Lev, A., ... Klein, C. (2020). Human FCHO1 deficiency reveals role for clathrin-mediated endocytosis in development and function of T cells. Nature Communications, 11(1), Article 1031. https://doi.org/10.1038/s41467-020-14809-9

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

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.",

author = "Marcin {\L}yszkiewicz and Natalia Zi{\c e}tara and Laura Frey and Ulrich Pannicke and Marcel Stern and Yanshan Liu and Yanxin Fan and Jacek Pucha{\l}ka and Sebastian Hollizeck and Ido Somekh and Meino Rohlfs and Tuğba Yilmaz and Ekrem {\"U}nal and Musa Karakukcu and T{\"u}rkan Patiroğlu and Christina Kellerer and Ebru Karasu and Sykora, {Karl Walter} and Atar Lev and Amos Simon and Raz Somech and Joachim Roesler and Manfred Hoenig and Keppler, {Oliver T.} and Klaus Schwarz and Christoph Klein",

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Łyszkiewicz, M, Ziętara, N, Frey, L, Pannicke, U, Stern, M, Liu, Y, Fan, Y, Puchałka, J, Hollizeck, S, Somekh, I, Rohlfs, M, Yilmaz, T, Ünal, E, Karakukcu, M, Patiroğlu, T, Kellerer, C, Karasu, E, Sykora, KW, Lev, A, Simon, A, Somech, R, Roesler, J, Hoenig, M, Keppler, OT, Schwarz, K & Klein, C 2020, 'Human FCHO1 deficiency reveals role for clathrin-mediated endocytosis in development and function of T cells', Nature Communications, vol. 11, no. 1, 1031. https://doi.org/10.1038/s41467-020-14809-9

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T1 - Human FCHO1 deficiency reveals role for clathrin-mediated endocytosis in development and function of T cells

AU - Łyszkiewicz, Marcin

AU - Ziętara, Natalia

AU - Frey, Laura

AU - Pannicke, Ulrich

AU - Stern, Marcel

AU - Liu, Yanshan

AU - Fan, Yanxin

AU - Puchałka, Jacek

AU - Hollizeck, Sebastian

AU - Somekh, Ido

AU - Rohlfs, Meino

AU - Yilmaz, Tuğba

AU - Ünal, Ekrem

AU - Karakukcu, Musa

AU - Patiroğlu, Türkan

AU - Kellerer, Christina

AU - Karasu, Ebru

AU - Sykora, Karl Walter

AU - Lev, Atar

AU - Simon, Amos

AU - Somech, Raz

AU - Roesler, Joachim

AU - Hoenig, Manfred

AU - Keppler, Oliver T.

AU - Schwarz, Klaus

AU - Klein, Christoph

PY - 2020/2/25

Y1 - 2020/2/25

N2 - 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.

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

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