Caspase 7 is a cysteine aspartate protease, belonging to the larger caspase family of proteins that control various cellular processes. It is a member of the peptidase C14A family.
Caspase 7’s Role in Programmed Cell Death
Caspase 7’s primary function is in programmed cell death, also known as apoptosis. Apoptosis is a natural, controlled process where cells are systematically dismantled and removed without causing inflammation in the surrounding tissues. This process is essential for normal development, tissue renewal, and eliminating old, damaged, or unwanted cells.
Caspase 7 acts as an “executioner caspase.” Once activated, it cleaves specific proteins within the cell, leading to the characteristic changes observed during apoptosis, such as DNA fragmentation and changes in cell shape. One notable protein it cleaves is poly(ADP-ribose) polymerase (PARP), a protein involved in DNA repair.
How Caspase 7 is Activated and Controlled
Caspase 7 begins as an inactive precursor, or proenzyme, and requires specific signals to activate. Its activation involves proteolytic processing by upstream enzymes called “initiator caspases.” These initiator caspases, such as caspase 8, caspase 9, and caspase 10, cleave caspase 7 at specific aspartic residues, transforming it into its active form, a heterotetramer composed of two large and two small subunits.
The activation of caspase 7 is part of two main apoptotic pathways: the extrinsic (death receptor) pathway and the intrinsic (mitochondrial) pathway. In the extrinsic pathway, external signals like death receptor ligands bind to receptors on the cell surface, leading to the activation of initiator caspases like caspase 8 and 10, which then activate caspase 7. The intrinsic pathway is triggered by internal cellular stress, such as DNA damage, leading to the release of mitochondrial proteins that activate caspase 9, which then activates caspase 7. Tight regulatory mechanisms prevent accidental activation and unwanted cell death, with inhibitors of apoptosis proteins (IAPs) playing a role in this control.
Caspase 7 in Health and Disease
The proper regulation of Caspase 7 activity is important for health, and its dysregulation can contribute to various diseases. In cancer, for instance, Caspase 7 can act as a tumor suppressor by promoting the death of abnormal cells. However, some cancer cells develop resistance to chemotherapy by downregulating other executioner caspases, such as Caspase 3, making them more reliant on Caspase 7 for apoptosis.
In such cases, Caspase 7’s activity might be inhibited by proteins like XIAP (X-linked inhibitor of apoptosis protein), which prevents cancer cell death. Researchers are exploring ways to “unshackle” Caspase 7 by disrupting its interaction with inhibitors like XIAP, potentially restoring programmed cell death in drug-resistant cancers. While the exact mechanisms are still under investigation, balancing Caspase 7 activity is an area of ongoing research for therapeutic interventions in conditions where cell death or survival is imbalanced.
Distinctions Among Caspase Family Members
The caspase family is broadly divided into two groups based on their function: initiator caspases and executioner caspases. Initiator caspases, including Caspase 8, 9, and 10, begin the apoptotic cascade in response to various stimuli. Executioner caspases, such as Caspase 3, 6, and 7, are then activated by initiator caspases and carry out the proteolytic cleavage of cellular substrates, leading to the cellular changes associated with apoptosis.
While Caspase 7 shares overlapping functions with other executioner caspases, particularly Caspase 3, they are not entirely redundant. Both cleave similar substrates like PARP, but studies indicate that Caspase 3 is more promiscuous in its substrate cleavage and is considered a major executioner in the demolition phase of apoptosis. Caspase 7 has been observed to contribute to reactive oxygen species (ROS) production and aid in cell detachment during apoptosis, while Caspase 3 helps limit ROS production. These distinctions suggest that while they cooperate, they also have specialized roles within the cell death machinery.