Lecture 5 "Unfolded Proteins Response"

• normal (physioligical) conditions

• environmental stresses

• metabolic stresses

• aging

• cancer

• inefficient protein biogenesis

• mutant proteins

• excess of unassembled subunits of oligomeric complexes

• inefficient translocated precursor protein

• elevted temperatures

• exposure to chemicals

• viran and bacterial infections

• tissue injury

  
  

• nutrient imbalance

• production of ROS

• mitochrondrial dysregulation

high cell division and mutation rates

• gradudal decrease of protein homeostasis capacity

• accumulation of mutated and oxidatively damaged proteins

• Protein aggregation > toxicity > cell death

1. sensing

2. signal transmission

3. trasnciption factor

4. genes related to protein folding and degradation

• bzip has to be syntheiszed in the ER and has a TM donaun

• happens at protein lebel

• has no TF and no RNAse activity

  1. Phosphorylation of elF2a

  2. inhibition of elF2B

  3. Reduced elF2: Reduction of protein load in ER

• Chaperones

• Increase ERAD

• Reduce protein load

• Expand ER

• in primates: IRE, PERK and ATF

• animals: IRE, PEK and Atf

• funghi: ire

• HSP100 and resolubilization

• degradation (autophagy, proteosomal degredation)

• Plasma Cells:

  • Differentiation of B cells into antibody secreting plasma cells is accompanied by a large expansion of the ER

    • Atf6 is activated during plasma cell differentiation but PERK is inactive

    • Customization of UPR so that ER expansion accomodates sustained high levels of secretion t´rather than a need to limit the protein folding burden via translationa repression

• Pancreatic cells

  • beta cells of the endocrine pancreas are responsible for secreting insulin in response ti glucose

  • ß-cells appear to be heavily reliant on PERK

1. Import

2. Chaperone bindig

3. Glycosilation

4. Folding

1. recognition

2. ubiquitination

3. retrotranslocation

4. degradation

• ERj1 inhibits initiation of protein syntheisis in the absence of BiP

• double role:

  1. activating Bzip60

  2. degreade ER localized mRNA

  = less protein translation

• increasing ER size through membrane syntheis is an integral yet distinct part of the cellular program to overcome ER stress

• XBP1-deficent B cells are unable to differentiate into antobody-producing plasma cells

• antibody secretion is directly dependent on XBP1 splicing is stimulared B cells