Lecture 18

• Programmed Cell Death (PCD)

  A sequence of genetically programmed events leading to the systematic elimination of cells
• Programmed Cell Death

  • Crucial for maintaining cellular homeostasis and development across various organisms
• Necrosis

  Triggered externally by non-specific factors, characterized by moderate chromatin condensation, swelling of cytoplasmic organelles, and rupture of the plasma membrane, leading to inflammation and collateral damage, lacks a genetic programming and integrated signal transduction
• Apoptosis

  Genetically programmed cell death with controlled, active processes, cell contents are contained, reducing immune sequelae
• Distinguishing between necrosis and apoptosis is important; however, in plants and some animal scenarios, PCD can still trigger inflammatory responses
• Programmed Cell Death in Plants

  Developmental examples: Unisexual flower development, Microsporogenesis and megasporogenesis
• Programmed Cell Death in Animals

  1. Developmental examples: Mouse forelimb development, Drosophila metamorphosis

  2. Elimination of dangerous and abnormal cells, such as autoreactive lymphocytes, Maintaining a balance between cell creation and death in humans
• Caspase Activation

  Assembly of an activating complex with initiator procaspases, leading to the activation of executioner caspases, tightly regulated through autocleavage and rearrangement
• Intrinsic Apoptosis

  Triggered by internal cell stress like DNA damage, ER stress, marked by mitochondrial outer membrane permeabilization (MOMP) and release of cytochrome c
• Apoptosome

  Forms when cytochrome c activates Apoptotic Protease Activating Factor-1 (Apaf-1), recruits initiator procaspase 9 via CARD interactions, leading to the initiation of the caspase cascade and apoptosis
• Regulation of Intrinsic Apoptotic Pathway

  • Pro-apoptotic factors: Bax, Bak, BH3-only proteins
  • Anti-apoptotic factors: Bcl-2, Bcl-XL
  • Regulation of BH3-only proteins: Controlled by survival signals through post-translational modifications
• Bcl-2 Family Proteins

  Play a dual role, with members that either promote or inhibit apoptosis, regulate the release of cytochrome c and other pro-apoptotic factors through interactions at the mitochondrial membrane, the balance between pro-apoptotic and anti-apoptotic members determines the cell's susceptibility to apoptosis
• Execution of Apoptosis

  1. Initiation: Activation of initiator caspase 9 within the apoptosome

  2. Executioner Caspases: Caspase 3, 6, and 7 are critical, cleave a variety of substrates, leading to the biochemical and morphological changes associated with apoptosis
• p53 Role

  Regulates the expression of Bax and other pro-apoptotic proteins, enhances the apoptotic response under stress conditions, plays a significant role in developmental apoptosis by regulating organogenesis
• Trophic Factors


  Neurotrophins like nerve growth factor (NGF) and their receptors (e.g., p75NTR) influence apoptosis, particularly in the nervous system, can promote cell survival or death depending on the cellular context and receptor interactions
• Extrinsic Apoptosis

  Triggered by external signals, specifically through death receptors on the cell surface, leads to the formation of a death-inducing signaling complex (DISC)
• Death Receptors and Ligands

  • TNF Family Ligands and Receptors: TNF and TNF receptors (TNF-R1, TNF-R2)
  • CD95 (FAS) and CD95L (FAS Ligand)
• Extrinsic Apoptotic Pathway

  1. Building Death Effector Filaments: Binding of FAS to FASL recruits FADD, which recruits procaspase 8 or 10 to the DISC, activating them by proximity

  2. Activation of Caspases: CASP8 and CASP10 are initiator caspases, can cleave and activate Bid, also directly activate executioner caspases (CASP3, CASP6, CASP7)
• Regulation of Extrinsic Pathway

  • c-FLIP Proteins: Regulate the activity of CASP8 and CASP10
  • Soluble Decoy Receptors (e.g., DcR3): Compete with death receptors for binding to ligands, modulating the strength and outcome of the apoptotic signal
• Interaction of Autophagy and Apoptosis

  1. FLIPs can interact with Beclin-1, a key protein in autophagy, influencing its stability and function, Beclin-1 can upregulate the activity of Bcl-2 and Bcl-XL
• PANoptosis


  Describes the complex scenario where multiple programmed cell death pathways, including pyroptosis, apoptosis, and necroptosis, are activated simultaneously, highly inflammatory and integrates various molecular mechanisms and signaling pathways
• Necroptosis


  A form of programmed necrotic death that can be triggered by signals such as TNF-R1 activation, results in the loss of plasma membrane integrity and is highly inflammatory, involves the activation of RIPK1, RIPK3, and MLKL
• Pyroptosis


  Characterized by the activation of CASP1, which forms part of the inflammasome, a crucial complex in inflammatory responses, CASP4 and CASP5 activation also involves the inflammasome and leads to the activation of gasdermin D, which forms pores in the cell membrane, exacerbating inflammation
• Linking Necroptosis, Pyroptosis, and Apoptosis

  The pathways of necroptosis, pyroptosis, and apoptosis can be interconnected through molecular interactions that cross-regulate and influence each other, components like FADD and RIPK1 play roles in both necroptosis and apoptosis, depending on the cellular context and the nature of the signals received