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Perforin/granzyme apoptosis pathway
- 2. WWW.CREATIVE-DIAGNOSTICS.COM Perforin/granzyme apoptosis pathway is the primary signaling pathway used by cytotoxic lymphocytes to eliminate virus- infected and/or transformed cells. Studies in gene-disrupted mice indicate that perforin, in combination with granzyme, could induce apoptosis. It is vital for cytotoxic effector function and has an indispensable, but an undefined role in granzyme-mediated apoptosis.
- 3. WWW.CREATIVE-DIAGNOSTICS.COM What is Perforin What is Granzyme Process of Perforin/Granzyme Pathway Regulation of Perforin/Granzyme Pathway Perforin/Granzyme Apoptosis Pathway in Disease
- 4. WWW.CREATIVE-DIAGNOSTICS.COM Perforin is a pore-forming protein and also known as cytoplasmic granule toxins. Perforin and Granzyme Granzyme is a family of structurally related serine proteases stored within the cytotoxic granules of cytotoxic lymphocytes (CLs).
- 5. WWW.CREATIVE-DIAGNOSTICS.COM Perforin and granzyme induce target-cell apoptosis cooperatively. Granzyme is necessary for triggering apoptosis of target cells, but they depend on being appropriately delivered by perforin. Both perforin and granzyme bind to the target-cell surface as part of a single macromolecular complex associated with serglycin, which further diminishes the probability of passive diffusion of granzymes.
- 6. WWW.CREATIVE-DIAGNOSTICS.COM The functions of granzymes A and B in inducing target-cell apoptosis have been investigated extensively in vitro, and they are better understood than the role of perforin at the molecular level. M A B H K Granzyme
- 11. WWW.CREATIVE-DIAGNOSTICS.COM 1 The perforin pathway is involved intimately in defense against viral pathogens and transformed cells. 2 Perforin is instrumental in the pathogenesis of certain autoimmune disease models, such as insulin-dependent diabetes in non-obese diabetic (NOD) mice, but it might suppress other autoimmune diseases, including experimental autoimmune encephalomyelitis (EAE). 3 The perforin/granzyme apoptosis pathways that regulate granule polarization and exocytosis are being determined, and these pathways might be disrupted by the interaction of cancer cells with some cytotoxic lymphocytes. Perforin/Granzyme Apoptosis Pathway in Disease
- 12. WWW.CREATIVE-DIAGNOSTICS.COM Do you want to know more about protein phosphorylation? Do not hesitate to contact us for any questions. Email us at info@creative-diagnostics.com Website: http://www.creative- diagnostics.com/ Any questions? Do not hesitate to contact us. Email us at info@creative-diagnostics.com Website: www.creative-diagnostics.com
Editor's Notes
- We are going to mainly focus on five parts to talk about Perforin Granzyme Apoptosis Pathway
- In humans, there are granzyme A, B, H, K, and M, while in mice there are granzyme A, B, C, D, E, F, G, K, L, M, and N.
- Once secreted by cytotoxic lymphocytes, granzymes enter into target cells, which is a vital step in cell death. The major lytic proteins packaged within the granules are different granzymes and the pore-forming protein perforin, which facilitates the internalization of granzymes by cells.
- In Cytoplasm, Granzyme B mainly triggers caspase activation indirectly, rather than by direct caspase processing. It achieves this by directly activating Bid. Bid together with pro-apoptotic BCL-2 family Bax and/or Bak proteins result in the leakage of cytochrome c, into the cytosol. Cytochrome c release activates pro caspase-9, and by binding to apoptotic protease activating factor 1(Apaf-1), pro caspase-9 becomes mature caspase-9, which continues to form the apoptosome and activates downstream caspase-3. Activated caspase-3 is able to cleave specific substrates like ICAD, allowing the CAD to translocate to the nucleus to fragment DNA. Besides Bid, granzyme B can inactivate Mcl-1 which is a member of the anti-apoptotic Bcl-2 family to release protein Bim on the outer mitochondrial membrane. And granzyme B can also mediate the effector caspase-3 and initiator caspase-8 to regulate the apoptosis pathway. Contrast to granzyme B, granzyme M doesn’t dependent on mitochondrial to regulate, but granzyme M may activate granzyme B by the cleavage PI 9. Granzyme M also can directly cleave the ICAD to unleash CAD like granzyme B.
- Granzyme A induces loss of mitochondrial inner membrane potential and the release of reactive oxygen species ROS. In response to ROS, the ER-associated SET complex, including SET, Ape1, pp32, HMG2 and TREX1
- They translocate to the nucleus, where TREX1, HM23H1, CAD, LaminB are involved in DNA Fragmentation
- The perforin pathway is involved intimately in defense against viral pathogens and transformed cells. Perforin is instrumental in the pathogenesis of certain autoimmune disease models, such as insulin-dependent diabetes in non-obese diabetic (NOD) mice, but it might suppress other autoimmune diseases, including experimental autoimmune encephalomyelitis (EAE). The perforin/granzyme apoptosis pathways that regulate granule polarization and exocytosis are being determined, and these pathways might be disrupted by the interaction of cancer cells with some cytotoxic lymphocytes.