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Cellular FLICE-Inhibitory Protein Regulates Tissue Homeostasis

  • Hiroyasu NakanoEmail author
  • Xuehua Piao
  • Ryodai Shindo
  • Sachiko Komazawa-Sakon
Chapter
Part of the Current Topics in Microbiology and Immunology book series (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.

Keywords

Embryonic Lethality Death Effector Domain Germline Deletion Murine Fibrosarcoma L929 Cell Cflip Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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

Notes

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.

Competing interests

The authors declare that they have no competing interests.

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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Hiroyasu Nakano
    • 1
    Email author
  • Xuehua Piao
    • 1
  • Ryodai Shindo
    • 1
    • 2
  • Sachiko Komazawa-Sakon
    • 1
  1. 1.Department of BiochemistryToho University School of MedicineTokyoJapan
  2. 2.Department of ImmunologyJuntendo University Graduate School of MedicineTokyoJapan

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