Abstract
cFLIP (cellular FLICE-like inhibitory protein) is structurally related to caspase-8 but lacks proteolytic activity due to multiple amino acid substitutions of catalytically important residues. cFLIP protein is evolutionarily conserved and expressed as three functionally different isoforms in humans (cFLIPL, cFLIPS, and cFLIPR). cFLIP controls not only the classical death receptor-mediated extrinsic apoptosis pathway, but also the non-conventional pattern recognition receptor-dependent apoptotic pathway. In addition, cFLIP regulates the formation of the death receptor-independent apoptotic platform named the ripoptosome. Moreover, recent studies have revealed that cFLIP is also involved in a non-apoptotic cell death pathway known as programmed necrosis or necroptosis. These functions of cFLIP are strictly controlled in an isoform-, concentration- and tissue-specific manner, and the ubiquitin-proteasome system plays an important role in regulating the stability of cFLIP. In this review, we summarize the current scientific findings from biochemical analyses, cell biological studies, mathematical modeling, and gene-manipulated mice models to illustrate the critical role of cFLIP as a switch to determine the destiny of cells among survival, apoptosis, and necroptosis.
Highlights
The homeostasis of our tissues, organs, and whole body is maintained by the continuous flow of birth, growth, differentiation, and death of cells
These results indicate that the functional Receptor interacting protein kinase 1 (RIPK1)-RIPK3-mixed lineage kinase-like protein (MLKL) axis and the balance of cFLIP isoforms are both critical determinants of cell fate switching among survival, apoptosis, and necroptosis
Wang et al [53] reported that C-terminus of HSP70-interacting protein (CHIP), another E3 ubiquitin ligase, was involved in the downregulation of cFLIPL induced by HSP90 inhibition in lung cancer cells
Summary
The homeostasis of our tissues, organs, and whole body is maintained by the continuous flow of birth, growth, differentiation, and death of cells. One physiological function of apoptosis is to kill and remove virus-infected cells in order to protect the hosts from viral propagation. In 1997, Thome et al [2] identified viral FLICE-inhibitory proteins (vFLIPs), which contained two death effector domains (DEDs) and interfered with apoptosis signaling through death receptors. Irmler et al [3] identified a highly related gene in human genome and named this as CFLAR (CASP8 and FADD-like apoptosis regulator). We will focus on three topics of the physiological roles of cFLIP as follows: (1) molecular functions of cFLIP in death receptor-mediated apoptosis pathway, ripoptosome formation, and necroptosis; (2) quantitative regulation of cFLIP by the ubiquitin-proteasome system; and (3) physiological roles of cFLIP to maintain tissue and systemic homeostasis in mammals. 2. Molecular Functions of cFLIP in Death Receptor-Mediated Apoptosis Pathway, Ripoptosome Formation, and Necroptosis
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
