Question: How do cells precisely regulate protein folding and degradation to maintain proteostasis?

Jacinta Nzilani answered on 17 Jul 2025:

Hey,
Picture a smart quality-control system inside cells, such that when proteins are made, they either fold correctly or get removed, preventing damage or imbalances, especially in proteases (protein-degrading enzymes).

1. Guiding or Rejecting Molecular Chaperones Decides the Fate
Protein folding is supervised by molecular chaperones, such as Hsp70 and Hsp90. They bind newly made or misfolded proteins and try to fold them correctly.

If a protein fails to fold after repeated chaperone cycles, it’s recognized as faulty. This triggers the protein triage system, in which chaperones and co-chaperones determine whether to fold or degrade proteins.
PMC

2. CHIP: The Co-Chaperone That Switches the Switch
A key player is CHIP (C-terminus of Hsp70-interacting protein), which partners with Hsp70/Hsp90 complexes. CHIP acts as a ubiquitin E3 ligase; it tags failed proteins with ubiquitin, marking them for destruction by the proteasome.

3. Ubiquitin & the Proteasome: The Protein Shredder
Tagged proteins are sent to the 26S proteasome, a giant molecular machine that essentially acts as a protein shredder, degrading them into amino acids. This is part of the ubiquitin‑proteasome system (UPS).

4. Decision-Making: Who Gets Saved and Who Gets Shredded?
Multiple models show how the cell “decides”:

The kinetic triage model says chaperones compete with E3 ligases for binding misfolded proteins.

Chaperone-cofactor balance matters: more pro-refolding cofactors favor rescue; more degradation cofactors (like CHIP) push toward destruction.
Wikipedia

5. Backup Systems: Autophagy + Compartmentalization
When some proteins aggregate, the cell can redirect them into compartments or use chaperone-mediated autophagy guided by BAG proteins and STUB1 to deliver damaged proteins to lysosomes for degradation.

6. Monitor & Match the Machinery
Even the assembly of the proteasome itself is controlled: special ATPase chaperones ensure the complex is properly built before activation. If misassembled, they’re removed or tagged for correction.

✅ Summary Table
Component: How It Regulates Protein Folding/Degradation
Hsp70 / Hsp90 & cofactors attempt to refold or flag misfolded proteins.
CHIP (E3 ubiquitin ligase) tags terminally misfolded proteins with ubiquitin for degradation.
26S Proteasome Degrades ubiquitinated proteins into amino acids
Proteostasis decision relies on chaperone/cofactor balance to decide fold or degrade
Autophagy systems Clear aggregated proteins or failed species via lysosomes
Proteasome assembly chaperones ensure that only properly assembled proteasomes become active

🦠 Why It Matters (especially for proteases!)
Proteases are powerful enzymes. Unregulated protease activity or failure to maintain them can lead to unwanted protein breakdown or cellular damage. Precise folding and degradation ensure that only correctly folded, needed proteases are active at the right time in the cell.
Cell.

Final Word:
Cells maintain a tight balance with folding helpers (chaperones) and degradation systems (UPS, autophagy). Cofactors like CHIP make crucial decisions; assembly chaperones ensure proper proteasome formation. Together, they guard protease levels and proteome health.