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Cellular FLICE-Inhibitory Protein Regulates Tissue Homeostasis

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Book cover Apoptotic and Non-apoptotic Cell Death

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 403))

Abstract

Cellular FLICE-inhibitory protein (cFLIP) is structurally related to caspase-8, but lacks its protease activity. Cflip gene encodes several splicing variants including short form (cFLIPs) and long form (cFLIPL). cFLIPL is composed of two death effector domains at the N terminus and a C-terminal caspase-like domain, and cFLIPs lacks the caspase-like domain. Our studies reveal that cFLIP plays a central role in NF-κB-dependent survival signals that control apoptosis and programmed necrosis. Germline deletion of Cflip results in embryonic lethality due to enhanced apoptosis and programmed necrosis; however, the combined deletion of the death-signaling regulators, Fadd and Ripk3, prevents embryonic lethality in Cflip-deficient mice. Moreover, tissue-specific deletion of Cflip reveals cFLIP as a crucial regulator that maintains tissue homeostasis of immune cells, hepatocytes, intestinal epithelial cells, and epidermal cells by preventing apoptosis and programmed necrosis.

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Abbreviations

BHA:

Butylated hydroxyanisole

Ciap:

Cellular inhibitor of apoptosis

cFLIP:

Cellular FLICE-inhibitory protein

CCCP:

Carbonyl cyanide m-chlorophenylhydrazone

DED:

Death effector domain

DPI:

Diphenyleneiodonium

EHV2:

Equine herpes virus-2

ERK:

Extracellular signal-regulated kinase

FADD:

Fas-associated protein with death domain

HHV-8:

Human herpes virus-8

IKKβ:

IκB kinase β

IEC:

Intestinal epithelial cell

JNK:

C-Jun N-terminal kinase

LUBAC:

Linear ubiquitination chain assembly complex

MCV:

Molluscum contagiosum virus

MLKL:

Mixed lineage kinase domain-like

MKK7:

Mitogen-activated protein (MAP) kinase kinase 7

MEK1:

MAPK/ERK kinase 1

Nec-1:

Necrostatin-1

NEMO:

NF-κB essential modulator

NF-κB:

Nuclear factor-κB

Nox:

NADPH oxidase

RIPK:

Receptor-interacting protein kinase

TAK1:

TGF-β-activated kinase 1

TCA:

Tricarboxylic acid cycle

TNF-α:

Tumor necrosis factor-α

TRAIL:

TNF-related apoptosis-inducing ligand

TRADD:

TNF receptor-associated death domain

TRAF:

TNF receptor-associated factor

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Acknowledgments

We thank CF. Ware, M. Miura, S. Yamazaki, and H. Imai for helpful comments on the manuscript. We also thank members of Department of Biochemistry, Toho University School of Medicine, for helpful discussion. RS is supported by a Research Fellowship from Japan Society for the Promotion of Science (JSPS), Japan. This work was supported in part by Grants-in-Aid from Scientific Research (B) (24390100) and Challenging Exploratory Research (25670167) from Japan Society for the Promotion of Science (JSPS), Scientific Research on Innovative areas (26110003) from a MEXT (Ministry of Education, Culture, Sports, Science and Technology), Japan, and research grants from NOVARTIS Foundation for the Promotion of Science, the Naito Science Foundation, the Uehara Science Foundation, and the Takeda Science Foundation.

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The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Department of Biochemistry, Toho University School of Medicine, 5-21-16 Omori-Nishi, Ota-Ku, Tokyo, 143-8540, Japan

    Hiroyasu Nakano, Xuehua Piao, Ryodai Shindo & Sachiko Komazawa-Sakon

  2. Department of Immunology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan

    Ryodai Shindo

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  1. Hiroyasu Nakano
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  2. Xuehua Piao
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  4. Sachiko Komazawa-Sakon
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Correspondence to Hiroyasu Nakano .

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  1. Biochemistry & Immunology, WPI Immunology frontier research center, Osaka University, Osaka, Japan

    Shigekazu Nagata

  2. Department of Biochemistry, Toho University School of Medicine, Tokyo, Tokyo, Japan

    Hiroyasu Nakano

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Nakano, H., Piao, X., Shindo, R., Komazawa-Sakon, S. (2015). Cellular FLICE-Inhibitory Protein Regulates Tissue Homeostasis. In: Nagata, S., Nakano, H. (eds) Apoptotic and Non-apoptotic Cell Death. Current Topics in Microbiology and Immunology, vol 403. Springer, Cham. https://doi.org/10.1007/82_2015_448

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