The Nedd4L ubiquitin ligase is activated by FCHO2-generated membrane curvature.

Autor:	Sakamoto Y; Department of Molecular Pharmacology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjyo, Kumamoto, 860-8556, Japan., Uezu A; Department of Molecular Pharmacology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjyo, Kumamoto, 860-8556, Japan., Kikuchi K; Department of Molecular Pharmacology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjyo, Kumamoto, 860-8556, Japan., Kang J; Faculty of Clinical Nutrition and Dietetics, Konan Women's University, 6-2-23 Morikita-machi, Kobe, 658-0001, Japan., Fujii E; Faculty of Clinical Nutrition and Dietetics, Konan Women's University, 6-2-23 Morikita-machi, Kobe, 658-0001, Japan., Moroishi T; Department of Molecular and Medical Pharmacology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjyo, Kumamoto, 860-8556, Japan., Suetsugu S; Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, 8916-5 Takayama-cho, Ikoma, 630-0192, Japan., Nakanishi H; Department of Molecular Pharmacology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjyo, Kumamoto, 860-8556, Japan. hnakanis@gpo.kumamoto-u.ac.jp.; Faculty of Clinical Nutrition and Dietetics, Konan Women's University, 6-2-23 Morikita-machi, Kobe, 658-0001, Japan. hnakanis@gpo.kumamoto-u.ac.jp.
Jazyk:	angličtina
Zdroj:	The EMBO journal [EMBO J] 2024 Oct 14. Date of Electronic Publication: 2024 Oct 14.
DOI:	10.1038/s44318-024-00268-1
Abstrakt:	The C2-WW-HECT domain ubiquitin ligase Nedd4L regulates membrane sorting during endocytosis through the ubiquitination of cargo molecules such as the epithelial sodium channel (ENaC). Nedd4L is catalytically autoinhibited by an intramolecular interaction between its C2 and HECT domains, but the protein's activation mechanism is poorly understood. Here, we show that Nedd4L activation is linked to membrane shape by FCHO2, a Bin-Amphiphysin-Rsv (BAR) domain protein that regulates endocytosis. FCHO2 was required for the Nedd4L-mediated ubiquitination and endocytosis of ENaC, with Nedd4L co-localizing with FCHO2 at clathrin-coated pits. In cells, Nedd4L was specifically recruited to, and activated by, the FCHO2 BAR domain. Furthermore, we reconstituted FCHO2-induced recruitment and activation of Nedd4L in vitro. Both the recruitment and activation were mediated by membrane curvature rather than protein-protein interactions. The Nedd4L C2 domain recognized a specific degree of membrane curvature that was generated by the FCHO2 BAR domain, with this curvature directly activating Nedd4L by relieving its autoinhibition. Thus, we show for the first time a specific function (i.e., recruitment and activation of an enzyme regulating cargo sorting) of membrane curvature by a BAR domain protein. (© 2024. The Author(s).)
Databáze:	MEDLINE
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