Model Answer
0 min readIntroduction
Caspases are a family of cysteine aspartic proteases that play a pivotal role in programmed cell death, or apoptosis, a fundamental process for multicellular organism development and homeostasis. Apoptosis is essential for eliminating damaged or unwanted cells without causing inflammation, unlike necrosis. Dysregulation of caspase activity is implicated in a wide range of diseases, including cancer, autoimmune disorders, and neurodegenerative diseases. Understanding the intricacies of caspase function is therefore crucial for developing therapeutic strategies targeting these conditions. This answer will detail the nature of caspase enzymes and their crucial role in orchestrating cell death.
What are Caspase Enzymes?
Caspases (Cysteine-ASPartic proteASES) are a family of proteases that cleave substrates at specific aspartic acid residues. They are synthesized as inactive pro-enzymes, called procaspases, which require activation through proteolytic cleavage. There are approximately 8-10 caspases in mammals, categorized into two main groups based on their function:
- Initiator Caspases (2, 8, 9, 10): These caspases initiate the apoptotic cascade by activating executioner caspases. They possess long prodomains that facilitate their activation by upstream signals.
- Executioner Caspases (3, 6, 7): These caspases are directly responsible for the dismantling of the cell by cleaving a variety of cellular substrates. They have short prodomains and are activated by initiator caspases.
Activation Pathways of Caspases
Caspase activation occurs through two major pathways: the intrinsic (mitochondrial) pathway and the extrinsic (death receptor) pathway.
Intrinsic (Mitochondrial) Pathway
This pathway is triggered by intracellular stress signals such as DNA damage, oxidative stress, or growth factor withdrawal. These signals lead to mitochondrial outer membrane permeabilization (MOMP), releasing cytochrome c into the cytoplasm. Cytochrome c binds to Apaf-1, forming an apoptosome complex, which then activates caspase-9 (an initiator caspase). Activated caspase-9 subsequently activates executioner caspases like caspase-3.
Extrinsic (Death Receptor) Pathway
This pathway is initiated by the binding of death ligands (e.g., TNF-α, FasL) to their corresponding death receptors (e.g., TNFR1, Fas) on the cell surface. This binding recruits adaptor proteins (e.g., FADD) and procaspase-8 (or procaspase-10) to form the Death-Inducing Signaling Complex (DISC). Within the DISC, procaspase-8 is activated, which then activates executioner caspases.
Role of Caspases in Cell Death
Once activated, executioner caspases initiate a cascade of proteolytic events that lead to the characteristic morphological changes of apoptosis:
- DNA Fragmentation: Caspase-activated DNase (CAD) is activated, leading to DNA cleavage between nucleosomes, resulting in the characteristic DNA laddering observed in apoptotic cells.
- Cytoskeletal Disruption: Caspases cleave cytoskeletal proteins like actin and lamin, causing cell shrinkage and blebbing.
- Cellular Blebbing: The plasma membrane undergoes blebbing, forming apoptotic bodies.
- Phosphatidylserine Externalization: Caspases activate scramblase, leading to the externalization of phosphatidylserine, a signal for phagocytosis by macrophages.
Caspase Dysfunction and Disease
Dysregulation of caspase activity is linked to several diseases:
- Cancer: Inhibition of caspases can lead to resistance to chemotherapy and promote tumor growth.
- Autoimmune Diseases: Defective apoptosis can result in the survival of autoreactive lymphocytes, contributing to autoimmune disorders like systemic lupus erythematosus (SLE).
- Neurodegenerative Diseases: Excessive activation of caspases can contribute to neuronal loss in diseases like Alzheimer's and Parkinson's disease.
- Ischemic Injury: Caspase activation plays a role in neuronal damage following stroke or myocardial infarction.
| Caspase | Pathway | Role |
|---|---|---|
| Caspase-2 | Intrinsic | Initiator; activated by cytoplasmic stress |
| Caspase-8 | Extrinsic | Initiator; activated by death receptors |
| Caspase-9 | Intrinsic | Initiator; activated by apoptosome |
| Caspase-3 | Both | Executioner; cleaves numerous substrates |
Conclusion
In conclusion, caspase enzymes are central regulators of apoptosis, a vital process for maintaining tissue homeostasis and eliminating damaged cells. Their activation through intrinsic and extrinsic pathways leads to a cascade of proteolytic events culminating in the characteristic features of programmed cell death. Dysregulation of caspase activity is implicated in a wide spectrum of diseases, highlighting their importance as therapeutic targets. Further research into the intricate mechanisms governing caspase function will undoubtedly lead to novel strategies for treating these debilitating conditions.
Answer Length
This is a comprehensive model answer for learning purposes and may exceed the word limit. In the exam, always adhere to the prescribed word count.