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Nat Commun. 2018 Oct 26;9(1):4457. doi: 10.1038/s41467-018-06985-6.

A FRET biosensor for necroptosis uncovers two different modes of the release of DAMPs.

Author information

1
Department of Biochemistry, Toho University School of Medicine, 5-21-16 Omori-Nishi, Ota-ku, Tokyo, 143-8540, Japan.
2
Hibernation Metabolism, Physiology, and Development Group, Environmental Biology Division, Institute of Low Temperature Science, Hokkaido University, Kita 19, Nishi 8, Kita-ku, Sapporo, Hokkaido, 060-0819, Japan.
3
Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Chiyoda-ku, Tokyo, 102-0075, Japan.
4
Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Bunkyo-ku, Tokyo, 113-0033, Japan.
5
Division of Cell Signaling and Cell Death, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
6
Department of Medical Biology, University of Melbourne, Parkville, VIC, 3050, Australia.
7
Laboratory of Molecular Biology and Immunology, Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, 6-3-1 Niijuku, Katsushika-ku, Tokyo, 125-8585, Japan.
8
Department of Food Science and Technology, Faculty of Applied Life Science, Nippon Veterinary and Life Science University, 1-7-1 Kyonancho, Musashino-shi, Tokyo, 180-8602, Japan.
9
Department of Physiology, Toho University School of Medicine, 5-21-16 Omori-Nishi, Ota-ku, Tokyo, 143-8540, Japan.
10
Department of Immunology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
11
Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Bunkyo-ku, Tokyo, 113-0033, Japan.
12
Department of Biochemistry, Toho University School of Medicine, 5-21-16 Omori-Nishi, Ota-ku, Tokyo, 143-8540, Japan. hiroyasu.nakano@med.toho-u.ac.jp.
13
Host Defense Research Center, Toho University School of Medicine, 5-21-16 Omori-Nishi, Ota-ku, Tokyo, 143-8540, Japan. hiroyasu.nakano@med.toho-u.ac.jp.

Abstract

Necroptosis is a regulated form of necrosis that depends on receptor-interacting protein kinase (RIPK)3 and mixed lineage kinase domain-like (MLKL). While danger-associated molecular pattern (DAMP)s are involved in various pathological conditions and released from dead cells, the underlying mechanisms are not fully understood. Here we develop a fluorescence resonance energy transfer (FRET) biosensor, termed SMART (a sensor for MLKL activation by RIPK3 based on FRET). SMART is composed of a fragment of MLKL and monitors necroptosis, but not apoptosis or necrosis. Mechanistically, SMART monitors plasma membrane translocation of oligomerized MLKL, which is induced by RIPK3 or mutational activation. SMART in combination with imaging of the release of nuclear DAMPs and Live-Cell Imaging for Secretion activity (LCI-S) reveals two different modes of the release of High Mobility Group Box 1 from necroptotic cells. Thus, SMART and LCI-S uncover novel regulation of the release of DAMPs during necroptosis.

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