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

Shin Murai, Yoshifumi Yamaguchi, Yoshitaka Shirasaki, Mai Yamagishi, Ryodai Shindo, Joanne M. Hildebrand, Ryosuke Miura, Osamu Nakabayashi, Mamoru Totsuka, Taichiro Tomida, Satomi Adachi-Akahane, Sotaro Uemura, John Silke, Hideo Yagita, Masayuki Miura and Hiroyasu Nakano ()
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Shin Murai: Toho University School of Medicine
Yoshifumi Yamaguchi: Hokkaido University
Yoshitaka Shirasaki: Japan Science and Technology Agency
Mai Yamagishi: The University of Tokyo
Ryodai Shindo: Toho University School of Medicine
Joanne M. Hildebrand: The Walter and Eliza Hall Institute of Medical Research
Ryosuke Miura: Toho University School of Medicine
Osamu Nakabayashi: Toho University School of Medicine
Mamoru Totsuka: Nippon Veterinary and Life Science University
Taichiro Tomida: Toho University School of Medicine
Satomi Adachi-Akahane: Toho University School of Medicine
Sotaro Uemura: The University of Tokyo
John Silke: The Walter and Eliza Hall Institute of Medical Research
Hideo Yagita: Juntendo University Graduate School of Medicine
Masayuki Miura: The University of Tokyo
Hiroyasu Nakano: Toho University School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06985-6

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