Cellular FLICE-Inhibitory Protein Regulates Tissue Homeostasis

  • Hiroyasu NakanoEmail author
  • Xuehua Piao
  • Ryodai Shindo
  • Sachiko Komazawa-Sakon
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 403)


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.


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.



Butylated hydroxyanisole


Cellular inhibitor of apoptosis


Cellular FLICE-inhibitory protein


Carbonyl cyanide m-chlorophenylhydrazone


Death effector domain




Equine herpes virus-2


Extracellular signal-regulated kinase


Fas-associated protein with death domain


Human herpes virus-8


IκB kinase β


Intestinal epithelial cell


C-Jun N-terminal kinase


Linear ubiquitination chain assembly complex


Molluscum contagiosum virus


Mixed lineage kinase domain-like


Mitogen-activated protein (MAP) kinase kinase 7


MAPK/ERK kinase 1




NF-κB essential modulator


Nuclear factor-κB


NADPH oxidase


Receptor-interacting protein kinase


TGF-β-activated kinase 1


Tricarboxylic acid cycle


Tumor necrosis factor-α


TNF-related apoptosis-inducing ligand


TNF receptor-associated death domain


TNF receptor-associated factor



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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