homeostasis

• Cellular homeostasis


  How cells deal with trash
• Protein degradation


  An important cellular process
• Consequences of failure to degrade / destroy misfolded or aggregated proteins

  • Amyloid-β deposits (Alzheimer's disease)
  • α-Synuclein inclusion (Parkinson's disease)
  • TDP-43 inclusion (amyotrophic lateral sclerosis, ALS, 漸凍人症)
• Progression of specific proteinaceous lesions in neurodegenerative diseases over time
• Neurodegenerative diseases


  • Alzheimer's disease
  • Parkinson's disease
  • ALS
• People with neurodegenerative diseases

  • Muhammad Ali, a professional boxer
  • Michael J Fox, a famous actor
• Primary Symptoms of Parkinson's Disease

  • Tremor at rest
  • Muscle rigidity
  • Stooped posture
  • Expressionless face
  • Slow movement (bradykinesia)
  • Poor balance and co-ordination
• Protein degradation


  • Quality control to destroy misfolded proteins, aggregated proteins and damaged proteins
  • Regular protein turn-over
• Different proteins vary enormously in their life-span
• Protein half-life


  • Ornithine decarboxylase: 11 minutes
  • δ-Aminolevulinate synthetase: 70 minutes
  • Catalase: 1.4 days
  • Tyrosine aminotransferase: 1.5 hours
  • Tryptophan oxygenase: 2 hours
  • Glucokinase: 1.2 days
  • Lactic dehydrogenase: 16 days
  • HMG CoA reductase: 3 hours

  
• The life-span of a protein may depend on the tissue type
• The life-span of a protein may be regulated
• The life-span of proteins in a cell are not all the same
• Protein degradation is an important cellular process
• Protein degradation takes place in the proteasome and lysosome
• Proteasome


  A large protein complex distributed all over the cell (nucleus +cytoplasm) that degrades misfolded proteins and short-lived proteins

  
• Lysosome


  An intracellular organelle distributed in the cytoplasm that degrades proteins, digests bacteria, damaged organelles, unhealthy cells, virus, etc.

  
• Ubiquitin (Ub)


  A small protein consisting of 76 amino acids that exists in all eukaryotic cells and is highly conserved. It is used to tag proteins for degradation.

  
• Ubiquitination pathway


  1. E1: ubiquitin-activating enzyme

  2. E2: ubiquitin-conjugating enzymes

  3. E3: ubiquitin ligases

  
• How proteasome distinguishes "bad" proteins from "good" proteins

  • Ubiquitin tags the "bad" proteins for degradation

  
• Ubiquitin contains 7 lysine residues that indicate it can be ubiquitinated itself</b>

  
• Key steps of protein digestion by proteasome

  • 19S cap contains ubiquitin receptor to recognize ubiquitinated proteins
  • 19S cap uses ATP hydrolysis to unfold the target protein
  • Unfolded target protein is pushed through the central cylinder to be cut into pieces

  
• Lysosome


  Stores a variety of digestive enzymes that function at acidic pH to digest ingested materials, bacteria, damaged organelles, etc.

  
• Functions of proteins on lysosome membranes

  • Proton pump uses ATP hydrolysis to pump protons into the lysosome
  • Transport proteins that transport the final products of digestion, such as amino acids, to the cytosol
  • Pumps and transporters are highly glycosylated to protect from proteases

  
• Multiple pathways that deliver materials to lysosomes

  1. Endocytosis

  2. Phagocytosis

  3. Secretory pathway

  4. Autophagy

  
• Ubiquitin also functions as a tag to bring proteins to lysosomes in the endocytic pathway

  
• Autophagy ("self-eating")


  • Quality control to remove damaged organelles and big protein complexes
  • Reconstruction for normal cell growth and in development
  • Adaptive response to stress such as starvation and infection
• Three principle types of autophagy

  • Microautophagy
  • Chaperone mediated autophagy
  • Macroautophagy (autophagy)
• Process of macroautophagy


  Substrates including damaged organelles, aggregated proteins, and infectious agents are delivered to lysosomes via double-membrane autophagosomes. Autophagosome then fuse with lysosomes to digest its content.

  
• Autophagy functions both as a tumor suppressor pathway that prevents tumor initiation and as a survival pathway that helps tumor cells endure metabolic stress and resist death triggered by chemotherapeutic agents
• Defects in autophagy promotes tumor growth
• How to test whether autophagy is important for cancer progression? Measure the fraction of mice that grow tumor at different days after injection.