Autophagy

•Definition: Autophagy is the process in which a cell

sequesters and recycles damaged organelles and
macromolecules ( eats its own contents)
What can activate Autophagy:
1. Nutrient Deprivation( low level
of a.acids)
2. Accumulation of long-living
proteins

What regulate Autophagy?

1. MTOR signaling pathway
2. Atgs genes/proteins
What Mechanism?
1. Atgs proteins create autophagic
vacuoles
2. Autophagic vacuoles fuse with
lysosomes and content is
digested
 Autophagy and Disease
1. Cancer: This is an area of active investigation, autophagy
can both promote cancer growth and act as a defense
against cancers.
2. Neurodegenerative disorders: In Alzheimer disease,
formation of autophagosomes is accelerated. In Huntington
disease, mutant protein huntingtin impairs autophagy.
3. Infectious diseases: Many pathogens are degraded by
autophagy; these include mycobacteria, Shigella spp., and
HSV-1. This is one way by which microbial proteins are
digested and delivered to antigen presentation pathways.
Macrophage-specific deletion of Atg5 increases
susceptibility to tuberculosis
4. Inflammatory bowel diseases: Studies have linked both
Crohn disease and ulcerative colitis to autophagy related
genes.
 Necroptosis
• Necroptosis was first recognized as a caspase-
independent form of cell death that can be triggered
by treatment with TNF only in the presence of a pan-
caspase inhibitors
• Main executing molecule of the process is called
RIPK3 - receptor-interacting protein kinase 3 (RIPK3)
• Necroptosis requires that the function of caspase 8 be
inhibited or disrupted.
• Unlike apoptosis, in which several of the highly
immunogenic intracellular proteins are sequestered in
the dead cell, necroptosis is a strong trigger of
innate and adaptive immune responses
Formation of the
Necrosome is key
point in the
induction of
Necroptosis

Molecular mechanism of
TNF-mediated necroptosis:
Cross-linking of TNFR1
by TNF causes
recruitment of RIP1
and RIP3 along with
caspase 8.
Inhibition of caspase
8, as may occur in
some viral infections,
allows RIP1 and RIP3
to initiate signals that affect
mitochondrial generation
of ATP and ROS. This
is followed by events
typical of necrosis.
 Key Concepts of Necroptosis
• Necroptosis resembles necrosis morphologically and
apoptosis mechanistically as a form of programmed cell
death.
• Necroptosis is triggered by ligation of TNFR1, and viral
proteins of RNA and DNA viruses.
• Necroptosis is caspase-independent but dependent on
signaling by the RIP1 and RIP3 complex.
• RIP1-RIP3 signaling reduces mitochondrial ATP
generation, causes production of ROS, and
permeabilizes lysosomal membranes, thereby causing
cellular swelling and membrane damage as occurs in
necrosis.
• Release of cellular contents evokes an inflammatory
reaction as in necrosis.
 Clinical implications of the
necroptosis
• Activation of Necroptosis will be beneficial
to induce strong anti-viral immune
response, e.g. for vaccination or for
treatment of viral infections
• Inhibition of Necroptosis will be beneficial
for treatment of ischemia-reperfusion
injury (MI, strokes, transplantation of
organs)
• More details:
Mediation of Programmed Cell Death by
Apoptosis or Regulated Necrosis

mitochondrial
permeability
transition
 Necrostatin1, Necrosulfonamide and Cyclosporine are
effective in the prevention of the Ischemia-reperfusion injury
 Pyroptosis
• Another form of programmed cell death
• Accompanied by the release of fever-inducing
cytokine IL-1 from ells
• Has some biochemical similarities with apoptosis
• Pyroptosis occurs in cells infected by microbes
(microbes in the cytoplasm of cells)!!!
• Involves activation of caspase-1, generation by
cell IL-1
• IL-1 recruit leukocytes to the site of infection
From : Cell death in the host response to infection Cell Death and Differentiation (2008) 15, 1339–1349;
doi:10.1038/cdd.2008.91; published online 20 June 2008 , K Labbé1 and M Saleh1,2
 Pathogen-induced host cell death

The type of death the cell undergoes depends on the nature of the pathogen, pathogen
load and site of infection.
Pyroptotic, apoptotic, autophagic or oncotic cells display a distinct set of morphological
and biochemical characteristics
Apoptosis and autophagy do not induce inflammation
Apoptosis, pyroptosis and autophagy are generally beneficial to the host, oncosis favors
pathogen dissemination