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Title: Conservation of structure and function in vertebrate c-FLIP proteins despite rapid evolutionary change
Authors: Sakamaki, Kazuhiro  kyouindb  KAKEN_id
Iwabe, Naoyuki
Iwata, Hiroaki  kyouindb  KAKEN_id
Imai, Kenichiro
Takagi, Chiyo
Chiba, Kumiko
Shukunami, Chisa
Tomii, Kentaro
Ueno, Naoto
Author's alias: 酒巻, 和弘
Keywords: Apoptosis
Pseudocatalytic triad
Issue Date: Sep-2015
Publisher: Elsevier B.V.
Journal title: Biochemistry and Biophysics Reports
Volume: 3
Start page: 175
End page: 189
Abstract: Cellular FLICE-like inhibitory protein (c-FLIP, gene symbol CFLAR) was first identified as a negative regulator of death receptor-mediated apoptosis in mammals. To understand the ubiquity and diversity of the c-FLIP protein subfamily during evolution, c-FLIP orthologs were identified from a comprehensive range of vertebrates, including birds, amphibians, and fish, and were characterized by combining experimental and computational analysis. Predictions of three-dimensional protein structures and molecular phylogenetic analysis indicated that the conserved structural features of c-FLIP proteins are all derived from an ancestral caspase-8, although they rapidly diverged from the subfamily consisting of caspases-8, -10, and -18. The functional role of the c-FLIP subfamily members is nearly ubiquitous throughout vertebrates. Exogenous expression of non-mammalian c-FLIP proteins in cultured mammalian cells suppressed death receptor-mediated apoptosis, implying that all of these proteins possess anti-apoptotic activity. Furthermore, non-mammalian c-FLIP proteins induced NF-κB activation much like their mammalian counterparts. The CFLAR mRNAs were synthesized during frog and fish embryogenesis. Overexpression of a truncated mutant of c-FLIP in the Xenopus laevis embryos by mRNA microinjection caused thorax edema and abnormal constriction of the abdomen. Depletion of cflar transcripts in zebrafish resulted in developmental abnormalities accompanied by edema and irregular red blood cell flow. Thus, our results demonstrate that c-FLIP/CFLAR is conserved in both protein structure and function in several vertebrate species, and suggest a significant role of c-FLIP in embryonic development.
Rights: © 2015 The Authors. Published by Elsevier B.V.
This is an open access article under the CC BY-NC-ND license (
DOI(Published Version): 10.1016/j.bbrep.2015.08.005
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