Abstract
Lipid rafts are subdomains of the cell membrane with distinct protein composition and high concentrations of cholesterol and glycosphingolipids. Raft proteins are thought to mediate diverse cellular processes including signal transduction. However, its cellular mechanisms remain unclear. Caveolin-1 (cav-1, marker protein of caveolae) has been thought as a switchboard between extracellular matrix (ECM) stimuli and intracellular signals. Flotillin-2/reggie-1(Flot-2) is another ubiquitously expressed raft protein which defines non-caveolar raft microdomains (planar raft). Its cellular function is largely uncharacterized. Our novel studies demonstrated that Flot-2, in conjunction with cav-1, played important functions on controlling cell death via regulating Fas pathways. Using Beas2B epithelial cells, we found that in contrast to cav-1, Flot-2 conferred cytoprotection via preventing Fas mediated death-inducing signaling complex (DISC) formation, subsequently suppressed caspase-8 mediated extrinsic apoptosis. Moreover, Flot-2 reduced the mitochondria mediated intrinsic apoptosis by regulating the Bcl-2 family and suppressing cytochrome C release from mitochondria to cytosol. Flot-2 further modulated the common apoptosis pathway and inhibited caspase-3 activation via up-regulating the members in the inhibitor of apoptosis (IAP) family. Last, Flot-2 interacted with cav-1 and limited its expression. Taken together, we found that Flot-2 protected cells from Fas induced apoptosis and counterbalanced the pro-apoptotic effects of cav-1. Thus, Flot-2 played crucial functions in cellular homeostasis and cell survival, suggesting a differential role of individual raft proteins.
Highlights
Apoptosis and necrosis are well known as two traditional cell death processes [1,2]
We investigated the cellular function of reggie1/Flotillin-2/formerly called reggie-1 (Flot-2), another lipid raft protein thought to locate in planar rafts
After exposure to hyperoxia (48h), we found that deletion of Flot-2 promoted hyperoxia-induced cell death, determined using CellTiter-Glo Luminescent Cell Viability Assay (Fig. 1B)
Summary
Apoptosis and necrosis are well known as two traditional cell death processes [1,2]. Many noxious stimuli induce either apoptosis or necrosis or both, depending on the cell type, the strength of stimulation and the presence of apoptosis inhibitors [3,4,5]. Fas has been reported to mediate both the caspase-dependent apoptotic death and the caspase-independent necrotic death [7] Both pathways are regulated through Fas associated death domain (FADD). Other death domain-containing proteins, such as FADD, interact with Fas [11,12,13] and promote the assembly of the death-inducing signaling complex (DISC)[14]. Intrinsic pathway can be stimulated by viral infections, toxins, free radicals or damage to DNA These stimuli induce the loss of mitochondrial transmembrane potential, leading to the release of proapoptotic proteins into the cytosol [15]. The mitochondrial (intrinsic) pathway is initiated by the release of pro-apoptotic proteins from the mitochondria to cytosol, including cytochrome c, apoptosis inducing factor (AIF), second mitochondria-derived activator of caspase (Smac)/direct inhibitor of apoptosis protein (IAP)-binding protein with low PI (DIABLO) etc. Smac/DIABLO counters the inhibitory effects of the IAPs and promotes caspase-3 activation [17]
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