Apoptoosi kaava a eräitä TM-RNF perheen jäseniä kuten FBAR , bifunctionaali apoptoosin säätelijä

3.3. Apoptosis

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4021871/
Link

Apoptosis is a complex, highly regulated cell-death process, which is mediated through extrinsic and intrinsic signal pathways. The extrinsic pathway is initiated by activation of the TNF family death receptors, such as Fas/CD95, TNFα receptor and TNF-related apoptosis-inducing ligand (TRAIL) receptor. Stimulation of the death receptors by ligand binding allows them to interact with the cytoplasmic adapter molecules, such as Fas-associated death domain (FADD) and TNF receptor-associated death domain (TRADD), through the cytoplasmic death domains. The death effecter domains (DEDs) of FADD and TRADD then recruit the DED-containing caspases, caspase-8 and caspase-10, which activate downstream caspases and proteases to induce apoptosis [131]. The intrinsic pathway is stimulated by various cellular stresses, including ER stress, oxidative stress, DNA damage and growth factor deprivation. These stimuli increase mitochondrial membrane permeability, leading to leakage of cytochrome c into the cytosol. This cytochrome c release activates caspases through binding to apoptosis protease activating factor-1 (Apaf-1) [132]. Members of the Bcl-2 family play important roles in the regulation of mitochondria-dependent apoptosis in both the extrinsic and intrinsic pathways. The pro-apoptotic Bcl-2 family members, Bax and Bak, are essential mediators of mitochondrial membrane permeability, whereas the anti-apoptotic members, Bcl-2 and Bcl-x_L, bind to the pro-apoptotic proteins and hinder apoptosis [132,133].

FBAR (BAR; RNF 47) (16p13.12) , Bifunctional apoptosis regulator, neuron protective in CNS ER.

 https://www.ncbi.nlm.nih.gov/gene/51283

 was identified as an inhibitor of Bax-induced apoptosis and is an ER-localized E3 enzyme predominantly expressed in neurons of the central nervous system [134,135]. Overexpression of BAR results in a protection of neural cells from apoptosis, whereas knockdown of BAR increases apoptosis [135]. The anti-apoptotic effect of BAR requires the transmembrane, sterile alpha motif (SAM) and DED-like domains, but not the RNF domain, suggesting that BAR E3 activity is not involved in the suppression of cell death [135]. The SAM domain binds to Bcl-2 and Bcl-x_L, thereby interfering with Bax-induced apoptosis. On the other hand, the DED-like domain interacts with caspase-8 and caspase-10, thereby inhibiting Fas-induced apoptosis [135]. Thus, BAR protects neuronal cells from apoptosis that is mediated by either the extrinsic or intrinsic pathway.
FBAR =  Bifunctional apoptosis regulator.

----p53, p21, p73   and E3 Ubiquitin ligase---

RNF144B (P53RFP; IBRDC2)(6p22.3)

The p53 tumor suppressor is known to induce apoptosis in response to oncogenic stress through the transactivation of apoptotic genes, including Bax [136]. Upon apoptotic stimuli, p53 promotes the expression of the RNF144B E3 enzyme, which interacts with the cell cycle regulator p21/WAF [137]. RNF144B may promote the ubiquitination and degradation of p21/WAF, thus facilitating a shift of cellular response from growth arrest to p53-mediated apoptosis [137,138]. However, a recent study by Sayan et al. [139] reported that RNF144B expression is upregulated by the p53-related transcription factor p73, but not by p53. There are two p73 isoforms encoding the TAp73 and ΔNp73 proteins with or without the transactivation domain, respectively. TAp73 is able to induce apoptosis, while ΔNp73 blocks p53- and p73-mediated transactivation [140,141]. In response to DNA damage, cells preferentially degrade ΔNp73, preventing its inhibitory effect and promoting TAp73-mediated apoptotic processes [142]. RNF144B targets both the p73 isoforms for ubiquitination, but ΔNp73 is degraded faster than TAp73. As a result, the relative levels of TAp73 are increased, allowing TAp73 to exert its pro-apoptotic activity [142]. In the steady state, RNF144B is localized mainly in the cytosol [137,139,143], but it is translocated to mitochondria during apoptosis [143]. This translocation requires the putative transmembrane domain of RNF144B and activated mitochondrial Bax [143]. RNF144B interacts with activated Bax and influences Bax ubiquitination and stability. Knockdown of RNF144B results in increased Bax levels and enhances cell sensitivity to apoptosis [143]. Although the precise function and regulatory mechanism of RNF144B has not been elucidated, the role of RNF144B in apoptosis is evident.

RNF182 appears to be a pro-apoptotic factor.

 RNF182 was identified as a brain-specific E3 enzyme that targets ATP6V0C, a component of vacuolar ATPase, for proteasomal degradation [144]. Its mRNA levels are elevated in the brain with Alzheimer disease and in NT2 neuron cells undergoing stress-induced apoptosis. Increased RNF182 expression makes the neuron cells highly sensitive to stress-induced apoptosis [144]. Although the downregulation of ATP6V0C is unlikely to contribute to neuronal apoptosis, it may facilitate the regulation of pH homeostasis in neuronal cells.

RFP2 (RNF77, TRIM13)(13q14.2)   also appears to be involved in the induction of apoptosis [145].

 UV irradiation stabilizes the RFP2 protein in HEK293 human embryonic kidney cells, leading to increased ubiquitination of the anti-apoptotic proteins Akt kinase and Mdm2, a cytosolic E3 enzyme of p53. Proteasomal degradation of Mdm2 and Akt enhances ionizing radiation-induced apoptosis by increasing p53 stability and by decreasing anti-apoptotic Akt signaling [145].

An increasing body of evidence indicates that breakdown of the lysosomal membrane triggers apoptosis. Increased lysosomal permeability results in a release of lysosomal proteases into the cytosol, and the released proteases stimulate the mitochondria-dependent apoptotic pathway with increased mitochondrial membrane permeability [146].

RNF152  (TM-RNF  family)

 is a C-terminally anchored E3 enzyme that undergoes proteasomal degradation by Lys48-linked self-ubiquitination [147]. Overexpressed RNF152 is localized to the lysosomes and has a pro-apoptotic activity in a manner dependent on its E3 activity, suggesting a possible role in lysosome-associated apoptosis [147].