Balance between short and long isoforms of cFLIP regulates Fas-mediated apoptosis in vivo

Proceedings of the National Academy of Sciences of the United States of America
Daniel R RamAlexander Poltorak

Abstract

cFLIP, an inhibitor of apoptosis, is a crucial regulator of cellular death by apoptosis and necroptosis; its importance in development is exemplified by the embryonic lethality in cFLIP-deficient animals. A homolog of caspase 8 (CASP8), cFLIP exists in two main isoforms: cFLIPL (long) and cFLIPR (short). Although both splice variants regulate death receptor (DR)-induced apoptosis by CASP8, the specific role of each isoform is poorly understood. Here, we report a previously unidentified model of resistance to Fas receptor-mediated liver failure in the wild-derived MSM strain, compared with susceptibility in C57BL/6 (B6) mice. Linkage analysis in F2 intercross (B6 x MSM) progeny identified several MSM loci controlling resistance to Fas-mediated death, including the caspase 8- and FADD-like apoptosis regulator (Cflar) locus encoding cFLIP. Furthermore, we identified a 21-bp insertion in the 3' UTR of the fifth exon of Cflar in MSM that influences differential splicing of cFLIP mRNA. Intriguingly, we observed that MSM liver cells predominantly express the FLIPL variant, in contrast to B6 liver cells, which have higher levels of cFLIPR. In keeping with this finding, genome-wide RNA sequencing revealed a relative abundance of FLIPL t...Continue Reading

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Citations

Dec 17, 2016·International Journal of Molecular Sciences·Jung-Chun LinYing-Ju Lin
Feb 15, 2018·International Journal of Molecular Sciences·Nancy Martinez-MontielRebeca Martinez-Contreras
Nov 2, 2018·Proceedings of the National Academy of Sciences of the United States of America·Joseph SarhanAlexander Poltorak
Dec 1, 2018·Journal of Cellular Physiology·Raedeh SaraeiAli Hassanzadeh
Dec 20, 2017·Oncotarget·Chandrasekhar PadmanabhanR Daniel Beauchamp
Jun 13, 2020·Journal of Leukocyte Biology·Pontus Orning, Egil Lien
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May 6, 2021·Genetics, Selection, Evolution : GSE·Emilio Mármol-SánchezMarcel Amills
Aug 8, 2021·Cells·Kuo-Chieh Liao, Mariano A Garcia-Blanco

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