Protein Quality Control Mechanisms in Eukaryotic Cells

Eukaryotic cells rely on an integrated network of surveillance pathways to maintain protein homeostasis, ensuring that nascent chains fold correctly, damaged polypeptides are recognised and misfolded species are removed. Molecular chaperones guide folding and prevent aggregation, while the ubiquitin–proteasome system tags aberrant proteins for degradation. In the endoplasmic reticulum (ER), specialised machinery detects folding failures and directs them into ER-associated degradation (ERAD) or, when aggregates accumulate, into selective ER autophagy (ER-phagy). Cytosolic quality control monitors orphan subunits and mislocalised precursors, employing ubiquitin ligases and adaptor complexes to eject these substrates from complexes or membranes. Central to many degradative routes is the hexameric AAA+ ATPase p97 (also known as VCP or Cdc48), which uses ATP hydrolysis to extract polyubiquitinated clients and hand them to the proteasome or autophagic machinery. When proteolytic capacity is exceeded, stress responses such as the unfolded protein response (UPR) adjust chaperone levels and degradation capacity. Collectively, these pathways safeguard cellular function, prevent toxic aggregate formation and contribute to disease resistance, with broad implications for neurodegeneration, metabolic disorders and cancer therapy.

Research from Nature Portfolio

Two complementary studies have illuminated how eukaryotic cells adapt ER quality control under physiological and stress conditions. In one, the interplay between ERAD and ER-phagy in adipocytes was dissected, revealing that when the SEL1L–HRD1 complex is compromised, ER fragments bearing misfolded clients are instead cleared by autophagy, coalescing into insoluble structures termed CERFs. This work demonstrates a sequential hierarchy of degradative routes and highlights phase-separation events influenced by redox and substrate composition. A second investigation applied cryo-EM and NMR to capture the ATP-driven conformational cycle of human p97 at near-atomic resolution. By resolving the transient ADP·Pi intermediate state, the study clarifies how active-site phosphate trapping initiates allosteric changes that coordinate subunit movements, underpinning p97’s ability to translocate and unfold substrates. Together, these advances deepen our molecular understanding of both ER protein disposal and the mechanochemical basis of p97-mediated extraction.

Protein Quality Control Mechanisms in Eukaryotic Cells publication trend

The graph below shows the total number of articles in protein quality control mechanisms in eukaryotic cells across all publications each year (not limited to Nature Index journals).

Technical terms

Proteostasis: The cellular equilibrium of protein synthesis, folding and degradation.

ER-associated degradation (ERAD): A pathway recognising misfolded ER proteins for retrotranslocation and proteasomal degradation.

ER-phagy: Selective autophagic clearance of ER fragments containing misfolded proteins or aggregates.

Ubiquitin–proteasome system: A mechanism where ubiquitin tags direct proteins to the proteasome for degradation.

AAA+ ATPase: A family of ATP-hydrolysing enzymes that remodel or extract protein substrates from complexes or membranes.

Chaperone: A protein that assists in the folding and assembly of other polypeptides without being part of the final structure.

Adaptors: Proteins that link specific substrates to degradation or remodelling machines, such as ubiquitin ligases or ATPases.

References

1. The mechanisms to dispose of misfolded proteins in the endoplasmic reticulum of adipocytes. Nature Communications (2023).
2. Characterizing ATP processing by the AAA+ protein p97 at the atomic level. Nature Chemistry (2024).
3. Mechanism of orphan subunit recognition during assembly quality control. Cell (2023).
4. Valosin containing protein (VCP): initiator, modifier, and potential drug target for neurodegenerative diseases. Molecular Neurodegeneration (2023).