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.
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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).
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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.
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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
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Any questions?
Do not hesitate to contact us.
Email us at info@creative-diagnostics.com
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Hinweis der Redaktion
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.
