Chapter 18 Cell Death.

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Presentation transcript:

Chapter 18 Cell Death

Cell Death Apoptosis Necrosis Necroptosis Autophagy Cornification

Apoptosis Cell death: billions of cells die every hours in a human adult body, important for development Apoptosis (one form of programmed cell death): cell suicide, proposed in 1970s  acceptance (20 years later)  Nobel prize in 2002 Occur from unicellular organisms to multicellular organisms (molecular mechanisms are distinct) Astonishing number of cell death: never cells, thymus (T cells), bone marrow (B cells and neutrophils), eye (photoreceptors), spleen

How many apoptotic cells?

Apoptosis Quality control process: eliminating abnormal, superfluous, nonfunctional and potentially dangerous cells (cancerous cells) Development (sculpt) and tissue homeostasis (change of aged, nonfunctional cells with new cells) Morphological and biochemical changes

Programmed cell death eliminates unwanted cells Programmed cell death eliminates unwanted cells, as seen in the development of mouse paw. Apoptosis is a form of programmed cell death, and it plays important role in normal development (e.g., tissue sculpturing)

Programmed cell death eliminates unwanted cells Apoptosis during the metamorphosis of a tadpole into a frog

Apoptosis Morphological and biochemical changes shrinkage and condense cytoskeleton collapse Disassembly of the nuclear envelope, nuclear chromatin condensation, DNA fragmentation blebs apoptotic bodies Phosphatidylserine exposure(eat me signal) Cytochrome C Loss of Mt membrane potential

Apoptosis

Apoptotic cells are morphologically and biochemically recognizable DNA Fragmentation

Molecular Mechanisms of Apoptosis

Apoptosis: intracellular proteolytic cascade mediated by caspases Intracellular machinery for apoptosis is similar in all animal cells Caspases: cysteine protease, Cleave after aspartate Procaspase: inactive caspase, activated by proteolytic cleavage Inflammation caspases: 1, 4, 5 Initiator caspases: 2, 8, 9, 10 (CARD in prodomain-assembled with adaptor proteins in activation complex for activation)

Apoptosis: intracellular proteolytic cascade mediated by caspases Executioner caspases: 3, 6, 7 (targets: nuclear lamins, DNA (endonucleases), cytoskeleton, cell-cell adhesion molecules. Activated by initiator caspases) Extrinsic and intrinsic pathway can activate a caspase cascade

Cell-surface death receptors activate the extrinsic pathway of apoptosis Ligand binding region, transmembrane region, death domain TNF receptor family Death domain Fas-Fas ligand (formation of DISC (Death inducing signal complex): signal  receptor  adaptor protein (FADD-FAS associated protein with death domain)  Caspase 8 or 10  activation of downstream proteins)

Cell-surface death receptors activate the extrinsic pathway of apoptosis

Cell-surface death receptors activate the extrinsic pathway of apoptosis Inhibitors of extrinsic pathway Decoy receptor: ligand binding domain, but not death domain FLIP: resembles initiator caspases, but lacks proteolytic domain, compete with caspase 8 and caspase 10 for binding site in the DISC

The intrinsic pathway of apoptosis depends on mitochondria Apoptosis: also activated from inside the cell Caused by injury, DNA damage, lack of oxygen, nutrients, or survival signals Release of mitochondrial intermembrane space proteins Cytochrome C: binding to Apaf1  form apoptosome  recruitment of procasepase (9)  activation of downstream proteins Extrinsic pathway  harness intrinsic pathway to amplify apoptotic signal

The intrinsic pathway of apoptosis depends on mitochondria

The intrinsic pathway of apoptosis depends on mitochondria Release of cytochrome C during apoptosis

Bcl2 proteins regulates the intrinsic pathway of apoptosis Bcl2 family proteins Tightly regulate intrinsic pathway Evolutionary conserved from worms to humans Controlling the release of cytochrome C and other intermembrane space proteins Pro-apoptotic VS anti-apoptotic proteins: bind each other, balance regulates determines live or death Contain Bcl2 homology domain (BH) Anti: Bcl2, Bcl2-XL (contains BH 1~4 domain), Pro: Bax, Bak, Bad, Bim, Puma, Noxa (two subfamily-BH123 or BH3 only)

Bcl2 proteins regulates the intrinsic pathway of apoptosis The three classes of Bcl2 proteins

Bcl2 proteins regulates the intrinsic pathway of apoptosis Action of BH123 protein during apoptosis Binding to the outer membrane Form oligomers helping the release of the proteins

Bcl2 proteins regulates the intrinsic pathway of apoptosis Action of anti-apoptotic proteins (Bcl2 and Bcl2-XL) Mainly located on the outer membrane Inhibit apoptosis by binding to pro-apoptotic proteins (preventing oligomerization of Bak)

Bcl2 proteins regulates the intrinsic pathway of apoptosis Action of pro-apoptotic proteins (BH3 only proteins) promotes apoptosis by binding to anti-apoptotic proteins promotes apoptosis by directly binding to pro-apoptotic proteins (helping trigger and aggregate pro-apoptotic proteins)

IAPs inhibit caspases Inhibitors of apoptosis Another intracellular regulators for apoptosis besides Bcl2 Identified first in certain insect viruses, found in most animal cells BIR (baculovirus IAP) domain: binds to active capases  inhibits activation of caspases or polyubiquitylates caspases Anti-IAP: IAP binding motif  binding to BIR domain of IAPs (balance between IAPs and anti-IAPs: determine live or death) Controversial for mammalian homologes IAP and anti-IAP (Smac, Omi): depletion of the genes  no effects on apoptosis

IAPs inhibit caspases Action of IAPs

IAPs inhibit caspases Action of anti-IAPs

Extracellular survival factors inhibit apoptosis in various ways Extracellular signals Death or survival signals Death signals: Fas ligands, thyroid hormone, BMP Survival factors (inhibit apoptosis): bind to cell-surface receptors  suppress apoptotic program by regulating members of Bcl2 family proteins (increase of anti-apoptotic protein production, inhibiting the function of pro-apoptotic proteins, phosphorylation of anti-IAPs)

Extracellular survival factors inhibit apoptosis in various ways Survival factor secretion during neuronal cell targeting

Extracellular survival factors inhibit apoptosis in various ways Mechanisms of action for survival factors during apoptosis

Phagocytes remove the apoptotic cells Who? - Professional and non-professional phagocytes When? - Form birth to death, throughout life in multi- cellular organisms Where? - essentially anywhere cell death occurs (thymus, eye, spleen, bone marrow) Why? - Initially thought of simply garbage disposal, recent studies imply a critical role for clearance of apoptotic cell in development and tissue homeostasis and in preventing autoimmune diseases and inflammatory diseases

Either excess or insufficient apoptosis can contribute to disease Excess apoptosis Tissue damage: heart attacks, strokes Insufficient apoptosis Autoimmune diseases Cancer: mutations in Bcl2, p53 and so on

Necrosis

Necrosis Accidental cell death by physical or chemical stress A form of cell injury that results in the premature death of cells by autolysis Passive processes Morphological and biochemical features are distinctive from those of apoptosis

Necrosis Features of necrotic cells Loss of membrane integrity Begins with swelling of cytoplasm and mitochondria Ends with total cell lysis No vesicle formation, complete lysis Disintegration of organelles No energy requirement Random digestion of DNA

Programmed Necrosis (necroptosis) Necrosis was regarded as an unregulated and uncontrollable process Evidence now reveals that necrosis can also occur in a regulated manner Physiological necrosis in vivo was also observed under various physiological settings including mammalian development and tissue homeostasis Death receptor, RIP1 and RIP3 are involved in these processes Necroptosis participates in the pathogenesis of diseases including ischaemic injury, neurodegeneration and viral infection An attractive target for the avoidance of unwarranted cell death

Programmed Necrosis (necroptosis)

Autophagy

Autophagy Auto-’self’, phagein-’to eat’ in Greek Processes to remove unnecessary or non-functional organelles through lysosomes Inhibit accumulation of damaged or non-functional organelles by degrading them Increase survival by maintaining energy levels at nutrient deficient conditions Type II programmed cell death (death mechanism vs survival mechanism)

Figure Q18-1 Molecular Biology of the Cell (© Garland Science 2008)

Figure Q18-2 Molecular Biology of the Cell (© Garland Science 2008)