Autophagy Flashcards
Lysosomes function:
degrade & recycle macromolecules
Functions for macroautophagy
- Re-cycle proteins and other macromolecules under conditions of nutrient deprivation- allow recycling of amino acids, nucleotides and fatty acids.
- Remove organelles- mitochondria and peroxisomes.
- Allow cell survival under stress conditions (growth factor deprivation, hypoxia etc.)
- Present antigens to MHC system
- Neuro-protection- e.g. remove protein aggregates to prevent neuronal damage in e.g. Huntington’s, Parkinson’s disease etc.
- Remove intracellular pathogens
- Aging- increased autophagy can extend life in worms and other model organisms
- Tumor suppression- e.g. an autophagy gene (Beclin 1) is a haploinsufficient tumor suppressor in mice.
- Tumor promotion- e.g. required for progression and (perhaps) metastasis.
- Inhibits apoptosis/ cell death but also kills cells. Type II programmed cell death.
autophagy is
how stuff is delivered to lysosomes
autophagy recycles proteins and other macromolecules under conditions of
under conditions of nutrient deprivation- allow recycling of amino acids, nucleotides and fatty acids.
autophagy removes _____
organelles- mitochondria and peroxisomes.
and intra cellular pathogens
autophagy allows cells to
survival under stress conditions (growth factor deprivation, hypoxia etc.)
autophagy presents
Present antigens to MHC system
autogphagy functions in neuro-protection: examples
e.g. remove protein aggregates to prevent neuronal damage in e.g. Huntington’s, Parkinson’s disease etc.
autophagy and aging:
increased autophagy can extend life in worms and other model organisms
autophagy and tumor suppression
e.g. an autophagy gene (Beclin 1) is a haploinsufficient tumor suppressor in mice.
autophagy and tumor promotion
e.g. required for progression and (perhaps) metastasis.
autophagy inhibits
apoptosis/ cell death but also kills cells. Type II programmed cell death.
autophagy is induced during times of
nutrient stress
Atg genes
regulate autophagy
autophagic process
- induction
- vesiiclenucleation
- vesicle expansion
- cargo targeting
- veiscle closure
- vesicle fusion with endosome
- vesicle fusions with lyosome
induction
nutrient starvation, growth factor–mediated starvation exposure to chemo drugs, like rapamycin
vesicle nucleation also called
phagophore
vesicle expansion also called
also called omegasome
examples of cargo targeting
LC3II and p62
when vesicle closure occurs, it is called
autophagosome
when the vesicle fuses with the endosome, called
amphisome
when the vesicles fuses with the lysosome, it is then called
autolysosome
What regulates autogphagy?
- amino acids ad other nutrients
- growth factors
- lipids
- everything that regulated the PI3 kinase pathway
- Multiple protein kinases
- tumor suppressor proteins like p53, positive and negative regulation
- mutated oncogenes like Ras (positive and negative regulation
Autophagy signaling often converges on the
mTOR pathway
Beclin-1 interacts with Bcl-xL via
a BH3 domain
The BH3 mimetic _____ and disrupts the ______
ABT 737
Beclin-1-Bcl-xl interaction
Some examples of anti-cancer agents that have been proposed to work by inducing autophagic cell death
- mTOR inhibitors
- Topoisomerase inhibitors
- Arsenic
- Radiation
- Vitamin D analogs
- Oncolytic viruses
- DNA alkylating agents
- HDAC inhibitors
- TRAIL
______ inhibitors induced caspase-independent, autophagic cell death
HDAC
knockout of autophagy can prevent
cell death
autophagic cell death is associated with formation of
autophagic vesicles
Autophagy is a
highly regulated process and likely important in many physiological and pathological processes.
Autophagy is Intimately associated with
apoptosis & cell death
autophagy can
kill cells or protect cells against nutrient deprivation induced stress, neurodegeneration and anti cancer agents
Macroautophagy
- form a double membrane vesicle that captures cytosolic components/organelles. Then fuse with lysosome where hydrolases degrade contents of autophagosome.
Chaperone-mediated–
recognition of specific proteins that contain a specific recognition sequence (based on amino acid sequence KFERQ). Direct binding and delivery to lysosome.
Describe process of macroautophagy.
- Activate a PI3K complex that allows nucleation of a membrane that will eventually form autophagosome.
- Regulation of protein conjugation events to extend membrane.
- Randomly capture, or specifically deliver cargo to the extending autophagosome, then join the membranes to close the vesicle.
- Fuse with lysosome.
- Recycle amino acids and other macromolecular precursors.
Describe rationale behind autophagy’s protective action against neurodegeneration.
- Aggregate-prone proteins (e.g. those with expanded stretches of glutamine residues in diseases like Huntington’s disease) will cause neuronal cell death.
- Autophagy degrades the aggregate-prone proteins (perhaps after they have started to form small aggregates).
- No toxic stimulus, no neuronal cell death.
Identify mechanisms by which apoptosis induction and autophagy are connected.
Many proteins - e.g. Bcl-2 - that regulate apoptosis/ cell death, also control autophagy--remember, this could create problems in interpreting results of therapeutic interventions designed to target these proteins. Apoptotic proteases (caspases) can cleave essential autophagy regulators inactivating them and therefore blocking the process of autophagy. In some cases, -e.g. with starvation-induced cell death, it is easy to see why autophagy would protect– it provides essential nutrients at least in the short term. In others, e.g. stress-induced cell death from chemotherapy etc. its less clear why autophagy would be protective.
Many proteins - e.g. _____ - that regulate apoptosis/ cell death, also control __________
Bcl-2
autophagy–remember, this could create problems in interpreting results of therapeutic interventions designed to target these proteins.
Apoptotic proteases (caspases) can _______.
cleave essential autophagy regulators inactivating them and therefore blocking the process of autophagy
In some cases, -e.g. with starvation-induced cell death, it is easy to see why autophagy would protect– _______
it provides essential nutrients at least in the short term.
In others, e.g. stress-induced cell death from chemotherapy etc. its less clear why autophagy would be protective.
