Lecture 4 " Protein Quality Control"

folding/trafficking, remodeling, aggregation/disaggregation, autophagy, or degradation

• no heat shock = proteins stay soluble

• heat shock = PACS (proein aggregates centers) and stress granules

• recovery = dissaggregaton

• Targeting of misfolded proteins to the JUNQ depends on ubiquitination state

• blocking ubiquitination of misfolded VHL redirects it to the IPOD and renders it insoluble

IPOD-CytoQ-INQ

a. Vacuole route

1. sequestered protein is tagged with HSP42

2. moves into CytoQS cargo

3. protein disaggregation via HSP70/HSP100

4. can be handled via chaperones or degradated via UPS

b. Autophagy path

1. dysfunctional 26S proeasome is tagged with HSP42

2. transport into CytoQs

3. transport/anchoring to Cue5 phagophre

4. transprt to vacuole

Benefit:

• protein is recovered

• fast response

Risks:

• chaperone verload

• misfolding/aggregation potential

Benefit:

• Amino acid recycling

• purges delerious species

• purges deleterious species

Risk:

• proteasome overload

• proteins not recovered

Benefit:

• Reduce their cytotoxicity

• Prevent exhaution of protein qualitycontrol machinery

• facilitate subsequent protein refolding by chaperones

• clearnace by the UPS or autophagy

• asymmetric inheritence of damaged proteins during cell division, formation o aggregation free daughter cells

Risks:

• Inclusions are difficult to clear

• May sequester non-specific proteins

a. retrogade movement

Aggregate is actively mved back towards the mother cell side, so it does not get passed into the bud

b. compartment stays attached to vacuole

Inclusion remains linked to the vacuole, which helps retai it in the mother cell during division

c. retention/anchoring model

compartment is held in place rather than actively transported, stays in mother-cell compartment instead of being inherited by teh daughter