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1. CASPASES Presented by : Chandini B
2 nd year M.Sc DOS in Molecular Biology
University of Mysore Manasagangotri . Guided by : Dr. Ragi Jadimurthy

2. Contents Apoptosis Introduction to caspases History Types of caspases Caspase activation Caspases in apoptosis Caspases in inflammation Caspase regulatory factors Caspase 8 deficiency Summary

3. Apoptosis Apoptosis is the process of programmed cell death. On an average 50 to 70 billion cells die each day due to apoptosis in the average human adult. Apoptosis is essential to embryonic development and the maintenance of homeostasis in multicellular organisms. Apoptosis is indeed essential to eliminate cells, Example: Cells infected with viruses Cells with DNA damage Cancer cells

4. Introduction to caspases Caspases (cysteine-aspartic proteases, cysteine- dependent aspartate-directed proteases) are a family of protease enzymes which plays an important role in programmed cell death and inflammation. Also known as Interleukin-1 beta-converting enzyme (ICE), the first human caspase to be identified. Synthesized in cells as precursors named procaspase with 32-56kDa. Activation of caspases ensures that the cellular components are degraded in a controlled manner, carrying out cell death with minimal effect on surrounding tissues. Caspase 1

5. History H. Robert Horvitz initially established the importance of caspases in apoptosis and found that the ced-3 gene is required for the cell death that took place during the development of the nematode C. elegans Horvitz and his colleague Junying Yuan found that the protein encoded by the ced-3 gene is cysteine protease with similar properties to the mammalian interleukin-1-beta converting enzyme (ICE) (now known as caspase 1) . The 2002 Nobel Prize in Medicine was awarded to Sydney Brenner, H. Robert Horvitz and John Sulston for their work identifying genes that control apoptosis. Howard Robert Horvitz Junying yuan

6. Types of caspases Caspases are broadly classified based on their roles In apoptosis: Initiator caspases: Initiator caspases are the first to be activated in response to a proapoptotic stimulus and are responsible for activating the effector caspases by limited proteolysis. - CASP2, CASP8, CASP9 ,CASP10. 2. Effector/Executioner caspases: The effector caspases are responsible for most of the substrate proteolysis required for apoptosis. - CASP3, CASP6 , CASP7 In inflammation - CASP1, CASP4, CASP5, CASP11, CASP12, CASP13 Other roles - CASP14

7. Domain structure of human caspases CARD : caspase recruitment domain DED : death effector domain

8. Caspase activation

9. Bax – b cell lymphoma associated x protein Apaf 1- apoptotic protease activating factor -1 Caspases in apoptosis

10. Extrinsic pathway of apoptosis TNF – tumor necrosis factor FADD- fas associated death domain TRADD - Tumor necrosis factor receptor type 1-associated DEATH domain protein

11. Caspases Major role CASP2 Activates CASP7, suppress tumor growth by inducing cell cycle arrest, apoptotic inducer. CASP8 Key regulator of apoptosis, suppress necroptosis . CASP9 Key player in intrinsic pathway, essential to eliminate cells by executing apoptotic death early in development stage. CASP10 Major mediator of FAS mediated apoptosis CASP3 Catalyzing the specific cleavage of many key cellular proteins, cell cycle proteins. CASP6 Meditates nuclear shrinkage, mediates inflammasome . CASP7 ROS production and aids in cell detachment. Major role of apoptotic caspases

12. Caspase regulating factors IAP Group of proteins that mainly act on the intrinsic pathway of programmed cell death, which can frequently lead to cancer or other effects for the cell if mutated or improperly regulated. Negative regulator of caspase. Proteins also contain RING or UBC domains which act by binding to major proapoptotic factors and ubiquitylating them.

13. BCL -2 The members of the Bcl-2 family are a group of crucial regulatory factors in apoptosis. According to functional and structural criteria, the members can be divided into two groups.
Group I proteins are all anti-apoptotic proteins, including Bfl1, Bcl-2, Bcl -w, Bcl -xL.
They all have four short Bcl-2 homology (BH) domains:BH1, BH2, BH3 and BH4.
Group II proteins are all proapoptotic proteins, including Bad, Bak , Bax etc.

14. Caspases in inflammation Caspases induces an inflammatory response on a transcriptional level. It promotes transcription of nuclear factor- κB , a transcription factor that assists in transcribing inflammatory cytokines such as IFNs, TNF, IL-6 and IL-8. Caspase-1 is key in activating pro-inflammatory cytokines; these act as signals to immune cells for recruitment to the site of damage. Caspase-1 therefore plays a fundamental role in the innate immune system. This enzyme is responsible for processing cytokines such as pro-Ilβ and pro-IL18, as well as secreting them. Caspase-4 and -5 have a unique role as a receptor, whereby it binds to LPS, this can lead to the processing and secretion of IL-1β and IL-18 cytokines

15. Caspase 8 deficiency Rare genetic disorder of the immune system which caused by mutation in the gene CASP8 that encodes caspase8. Autosomal recessive disorder. This causes impairment of lymphocytic apoptosis in humans leads to accumulation of lymphocytes in the lymphatic organs. Splenomegaly and lymphadenopathy may ensue as a result. Immunodeficiency is another manifestation of caspase-8 disease since the enzyme is important for lymphocyte activation. A definite therapy for this syndrome is hematopoietic stem cell transplantation (HSCT)

16. Summary Caspases are the cysteine aspartic proteases which plays an important role in programmed cell death and inflammation. There are 12 know caspases are present in mammals. 2 types of caspases present in apoptosis – initiator caspases and effector caspases.

17. Importance of caspases in apoptosis Cut off contact with surrounding cells
Reorganize cytoskeleton
Shut down DNA replication and repair
Interrupt splicing
Destroy DNA
Disrupt nuclear structure
Induce cell to display signals marking it for phagocytosis
Disintegrate cells into apoptotic bodies