Autophogy Flashcards
Autophagy
- takes molecules into the cell
- brings into the lysosome to be degraded
Macroautophagy
cell engulfs large things outside cell
- autophagosome takes it to the lysosome
Microautophagy
Lysosome eats something on its own
Chaperone-mediated autophagy
Protein brings molecule to the lysosome
Steps of autophagy
- vesicle nucleation of autophagosome
- vesicle elongation of autophagosome
- vesicle fusion of autophagosome
- degradation
Where can you inhibit autophagy
Vesicle nucleation
Vesicle elongation
Vesicle fusion
When is autophagy induced?
During times of stress
- biggest one is birth (subacute loss of nutrition, e.g. Atg7 knockout mice)
- starvation (e.g. sleeping during night)
What are the key roles of autophagy in adults?
- protection against infection and neurodegeneration
- keeps you alive during times of starvation (between meals)
What are some functions for (macro)autophagy?
- re-cycle proteins and other macromolecules under conditions of nutrient deprivation
- remove/recycle organelles (mitochondria and peroxisomes)
- allow cell survival under stress conditions)
- regulate antigen presentation to MHC system
- neuro-protection
- remove intracellular pathogens
- remove intracellular pathogens
- aging
- tumor suppression
- tumor promotion
- regulate apoptosis
What is an autophagosome?
double membrane vesicle that has already taken up molecules to be degraded that then joins with a lysosome
How can autophagy be assessed?
- electromicroscopy
- following autophagosome associated proteins
- western blots
- fluorescent markers (GFP tag)
What do ATG genes do?
- regulate autophagy but also other things
- more than 20 gene products required to form autophagosomes
- many of these molecules are potentially druggable
Do autophagy regulators do other things independent of autophagy?
yes
Are autophagy and apoptosis connected?Provide an example
yes
- caspase cleavage of Beclin amplifies apoptosis
- Beclin-1 functions as part of a protein complex regulated by Bcl-2 and Bcl-xL
What does BH3 mimetic ABT 737 do?
- disrupts Beclin-1-Bcl-xl interaction
- affects both pathways - autophagy and apoptosis (trials are starting and don’t understand how affecting both)
How does “autophagic” cell death occur?
- associated with formation of autophagic vesicles
- requires autophagic machinery (inhibited by knockdown of Beclin-1/Atg6)
- may be class where autophagy promotes death by making other death mechanisms (apoptosis and necrosis) easier
What is the best example of clear autophagy-mediated effect that could be of practical therapeutic relevance?
autophagy as a protection of aggregate prone proteins (e.g. neurodegeneration)
How can autophagy protect against neurodegeneration?
- diseases caused by aggregate prone proteins (Alzheimers, Huntington’s)
- increase autophagy - protect in vitro against cell death and in vivo against tissue damage
- can use rapamycin and derivates or other autophagy inducers as chemoprevention/treatment for neurodegenerative diseases
What can autophagy protect cells against?
- nutrient deprivation induced stress
- neurodegeneration
- anti-cancer agents
