Chlamydia pneumoniae

Apoptosis II: Beyond Cytochrome c; the Other Mitochondrial Proteins

Bio Anti-Diablo homolog, mitochondrial DIABLO Antibody

Leda with her children

Diablo homolog

This gene encodes a 130 Å-long, arch-shaped homodimer protein. The full-length protein product spans 239 residues, 55 of which comprise the mitochondrial-targeting sequence (MTS) at its N-terminal. However, once the full-length protein is imported into the mitochondria, this sequence is excised to produce the 184-residue mature protein.This cleavage also exposes four residues at the N-terminal, Ala-Val-Pro-Ile (AVPI), which is the core of the IAP binding domain and crucial for inhibiting XIAP. Specifically, the tetrapeptide sequence binds the BIR3 domain of XIAP to form a stable complex between SMAC and XIAP.The homodimer structure also facilitates SMAC-XIAP binding via the BIR2 domain, though it does not form until the protein is released into the cytoplasm as a result of outer mitochondrial membrane permeabilization.Thus, monomeric SMAC mutants can still bind the BIR3 domain but not the BIR2 domain, which compromises the protein’s inhibitory function.Meanwhile, mutations within the AVPI sequence lead to loss of function, though SMAC may still be able to perform IAP binding-independent functions, such as inducing the ubiquitinylation of XIAP.

Bax/Bak-dependent, Drp1-independent Targeting of X-linked Inhibitor of Apoptosis Protein (XIAP) into Inner Mitochondrial Compartments Counteracts Smac/DIABLO-dependent Effector Caspase Activation

Efficient apoptosis requires Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP), which releases death-promoting proteins cytochrome c and Smac to the cytosol, which activate apoptosis and inhibit X-linked inhibitor of apoptosis protein (XIAP) suppression of executioner caspases, respectively. We recently identified that in response to Bcl-2 homology domain 3 (BH3)-only proteins and mitochondrial depolarization, XIAP can permeabilize and enter mitochondria. Consequently, XIAP E3 ligase activity recruits endolysosomes into mitochondria, resulting in Smac degradation. Here, we explored mitochondrial XIAP action within the intrinsic apoptosis signaling pathway. Mechanistically, we demonstrate that mitochondrial XIAP entry requires Bax or Bak and is antagonized by pro-survival Bcl-2 proteins. Moreover, intramitochondrial Smac degradation by XIAP occurs independently of Drp1-regulated cytochrome c release. Importantly, mitochondrial XIAP actions are activated cell-intrinsically by typical apoptosis inducers TNF and staurosporine, and XIAP overexpression reduces the lag time between the administration of an apoptotic stimuli and the onset of mitochondrial permeabilization. To elucidate the role of mitochondrial XIAP action during apoptosis, we integrated our findings within a mathematical model of intrinsic apoptosis signaling. Simulations suggest that moderate increases of XIAP, combined with mitochondrial XIAP preconditioning, would reduce MOMP signaling. To test this scenario, we pre-activated XIAP at mitochondria via mitochondrial depolarization or by artificially targeting XIAP to the intermembrane space. Both approaches resulted in suppression of TNF-mediated caspase activation. Taken together, we propose that XIAP enters mitochondria through a novel mode of mitochondrial permeabilization and through Smac degradation can compete with canonical MOMP to act as an anti-apoptotic tuning mechanism, reducing the mitochondrial contribution to the cellular apoptosis capacity. Keywords: E3 ubiquitin ligase; X-linked inhibitor of apoptosis protein (XIAP); cell death; dynamin-related protein 1 (Drp1); mitochondria; mitochondrial apoptosis; mitochondrial outer membrane permeabilization (MOMP); tumor necrosis factor (TNF).

Leda and the swan

APAF1

Apoptotic protease activating factor 1, also known as APAF1, is a human homolog of C. elegans CED-4 gene. participates in the CASPASE 9 (CASP9)-dependent activation of CASP3 in the general apoptotic pathway.

smac

Smac/DIABLO is a mitochondrial protein that potentiates some forms of apoptosis, possibly by neutralizing one or more members of the IAP family of apoptosis inhibitory proteins. Smac has been shown to exit mitochondria and enter the cytosol during apoptosis triggered by UV- or γ-irradiation.

BCL-2

Bcl-2 (B-cell lymphoma 2), encoded in humans by the BCL2 gene, is the founding member of the Bcl-2 family of regulator proteins that regulate cell death (apoptosis), by either inhibiting (anti-apoptotic) or inducing (pro-apoptotic) apoptosis.

Bcl-2 homologous antagonist/killer

Bcl-2 homologous antagonist/killer is a protein that in humans is encoded by the BAK1 gene on chromosome 6.The protein encoded by this gene belongs to the BCL2 protein family. BCL2 family members form oligomers or heterodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein localizes to mitochondria, and functions to induce apoptosis. It interacts with and accelerates the opening of the mitochondrial voltage-dependent anion channel, which leads to a loss in membrane potential and the release of cytochrome c. This protein also interacts with the tumor suppressor P53 after exposure to cell stress. BAK1 is a pro-apoptotic Bcl-2 protein containing four Bcl-2 homology (BH) domains: BH1, BH2, BH3, and BH4. These domains are composed of nine α-helices, with a hydrophobic α-helix core surrounded by amphipathic helices and a transmembrane C-terminal α-helix anchored to the mitochondrial outer membrane (MOM). A hydrophobic groove formed along the C-terminal of α2 to the N-terminal of α5, and some residues from α8, binds the BH3 domain of other BCL-2 proteins in its active form。

Generally, the pro-apoptotic function of BAK1 contributes to neurodegenerative and autoimmune diseases when overexpressed and cancers when inhibited.[8] For instance, dysregulation of the BAK gene has been implicated in human gastrointestinal cancers, indicating that the gene plays a part in the pathogenesis of some cancers. BAK1 is also involved in the HIV replication pathway, as the virus induces apoptosis in T cells via Casp8p41, which activates BAK to carry out membrane permeabilization, leading to cell death.[14] Consequently, drugs that regulate BAK1 activity present promising treatments for these diseases. Recently, one study of the role of genetics in abdominal aortic aneurysm (AAA) showed that different BAK1 variants can exist in both diseased and non-diseased AA tissues compared to matching blood samples. Given the current paradigm that all cells have the same genomic DNA, BAK1 gene variants in different tissues may be easily explained by the expression of BAK1 gene on chromosome 6 and one its edited copies on chromosome 20

Eurynome

Oceanid, daughter of Ocean.

FADD

Fas-associated protein with death domain (FADD), also called MORT1, is encoded by the FADD gene on the 11q13.3 region of chromosome 11 in humans. FADD is an adaptor protein that bridges members of the tumor necrosis factor receptor superfamily, such as the Fas-receptor, to procaspases 8 and 10 to form the death-inducing signaling complex (DISC) during apoptosis. As well as its most well known role in apoptosis, FADD has also been seen to play a role in other processes including proliferation, cell cycle regulation and development.

DEATH DOMAIN

The death domain (DD) is a protein interaction module composed of a bundle of six alpha-helices. DD is a subclass of protein motif known as the death fold and is related in sequence and structure to the death effector domain (DED) and the caspase recruitment domain (CARD), which work in similar pathways and show similar interaction properties.DD bind each other forming oligomers. Mammals have numerous and diverse DD-containing proteins. Within these proteins, the DD domains can be found in combination with other domains, including: CARDs, DEDs, ankyrin repeats, caspase-like folds, kinase domains, leucine zippers, leucine-rich repeats (LRR), TIR domains, and ZU5 domains.

TRAIL

TRAIL shows homology to other members of the tumor necrosis factor superfamily. It is composed of 281 amino acids and has characteristics of a type II transmembrane protein. The N-terminal cytoplasmic domain is not conserved across family members, however, the C-terminal extracellular domain is conserved and can be proteolytically cleaved from the cell surface. TRAIL forms a homotrimer that binds three receptor molecules.

Fas ligand

Fas ligand (FasL or CD95L or CD178) is a type-II transmembrane protein that belongs to the tumor necrosis factor (TNF) family. Its binding with its receptor induces apoptosis. Fas ligand/receptor interactions play an important role in the regulation of the immune system and the progression of cancer.

MOMP, cell suicide as a BCL-2 family business

Apoptosis shapes development and differentiation, has a key role in tissue homeostasis, and is deregulated in cancer. In most cases, successful apoptosis is triggered by mitochondrial outer membrane permeabilization (MOMP), which defines the mitochondrial or intrinsic pathway and ultimately leads to caspase activation and protein substrate cleavage. The mitochondrial apoptotic pathway centered on MOMP is controlled by an intricate network of events that determine the balance of the cell fate choice between survival and death. Here we will review how MOMP proceeds and how the main effectors cytochrome c, a heme protein that has a crucial role in respiration, and second mitochondria-derived activator of caspase (SMAC), as well as other intermembrane space proteins, orchestrate caspase activation. Moreover, we discuss recent insights on the interplay of the upstream coordinators and initiators of MOMP, the BCL-2 family. This review highlights how our increasing knowledge on the regulation of critical checkpoints of apoptosis integrates with understanding of cancer development and has begun to translate into therapeutic clinical benefit. Cell Death and Differentiation (2018) 25, 46–55; doi:10.1038/cdd.2017.179; published online 20 October 2017 Halime Kalkavan1 and Douglas R Green*,1

Figure 1 The extrinsic and intrinsic apoptotic pathways. The extrinsic pathway is initiated by engagement of DRs via their respective ligands TNF, FASL/CD95L, or TRAIL. Together with the adaptor FAS-associated death-domain (FADD) protein and the initiator procaspase-8 (or -10) they form the death-inducing signaling complex (DISC). This assembly enables the dimerization and autoactivation of the initiator caspases, which in turn cleave and activate the executioner caspase-3 and -7, ultimately leading to apoptosis unless they are inhibited by XIAP. The intrinsic pathway can be engaged by diverse intracellular stresses that modulate BCL-2 family protein interactions that control the activation of the BCL-2 effector proteins BAX and BAK. Once activated, BAX and BAK cause MOMP, leading to the release of proapoptotic IMS proteins. Cytochrome c (Cyt c) engages APAF1 and induces its oligomerization, leading to apoptosome formation that recruits and activates the initiator procaspase-9. Active caspase-9 cleaves and activates the executioner caspase-3 and -7. Simultaneously with Cyt c, Smac is released from the IMS and inhibits XIAP. The extrinsic and intrinsic pathways are linked; caspase-8 can cleave the BH3-only protein BH3-interacting domain death agonist (Bid), leading to its active, truncated form tBid, which in turn activates BAX/BAK. Numbers in circles indicate the respective pro- and active caspase; interrupted circles represent active caspases

Pleione

The star, Pleione, is named after a character from Greek mythology, namely, the wife of the Titan Atlas. Pleione was an Oceanic nymph, one of the three thousand daughters of the Titans Oceanus and Tethys.

Pavonia, Leighton

TOILETTE

1533年，教皇的侄女凯瑟琳下嫁法王享利二世，成为了法国香水文化的始作俑者。她的专职香水师还在巴黎开了第一家香水公司。

Leda and swan, da vinci

coronavirus

Hercules and Hylas

Hylas and nymphs

Silenus

Hyades

Hyades

The Hyades were seven daughters of Atlas.

Antisense RNA

Antisense RNA (asRNA), also referred to as antisense transcript, natural antisense transcript (NAT) or antisense oligonucleotide, is a single stranded RNA that is complementary to a protein coding messenger RNA (mRNA) with which it hybridizes, and thereby blocks its translation into protein.

Aeneas

Blood wars

dungeon

GREEK MYTH EXPLAINED

Kennedy space center

The new book of knowledge

Rehder