Protein Quality Control and Degradation

Protein quality control is the set of cellular systems that monitor whether proteins are correctly folded and needed, and that remove those that are misfolded, damaged, or no longer required. The two principal degradation routes are the ubiquitin-proteasome system, which tags individual proteins for destruction, and autophagy, which delivers bulkier cargo to the lysosome. Together with synthesis and folding, these systems keep the proteome in balance.

Definition

Protein quality control and degradation is the cellular surveillance and disposal of proteins, in which misfolded, damaged, or surplus proteins are recognised and routed for destruction, chiefly through the ubiquitin-proteasome system and autophagy, maintaining the overall balance of the proteome (proteostasis).

Scope

This topic covers how cells recognise defective or surplus proteins, the ubiquitin-proteasome pathway, lysosomal degradation and autophagy, the endoplasmic-reticulum unfolded protein response, and the concept of proteostasis. It is a molecular reference and does not provide clinical guidance.

Core questions

• How does a cell recognise a protein that should be destroyed?
• How does the ubiquitin-proteasome system select and degrade individual proteins?
• When is autophagy used instead of the proteasome?
• How does the cell respond when misfolded proteins accumulate?

Key concepts

• Protein quality control
• Ubiquitin-proteasome system
• E1-E2-E3 enzymatic cascade
• 26S proteasome
• Autophagy and the lysosome
• ER-associated degradation
• Unfolded protein response
• Proteostasis

Key theories

Ubiquitin-mediated proteolysis

Selective protein degradation is achieved by covalently tagging substrates with chains of ubiquitin through an enzymatic cascade (E1, E2, E3), marking them for recognition and destruction by the 26S proteasome and thereby providing regulated, substrate-specific turnover.

Mechanisms

In the ubiquitin-proteasome system, an enzymatic cascade (an activating E1, a conjugating E2, and a substrate-selecting E3 ligase) attaches ubiquitin chains to target proteins, which the 26S proteasome then recognises and degrades into peptides (Hershko & Ciechanover, 1998; Pickart, 2001). Bulkier or aggregated material and whole organelles are instead enclosed and delivered to the lysosome by autophagy (Mizushima & Komatsu, 2011). In the endoplasmic reticulum, accumulation of misfolded proteins triggers the unfolded protein response, which adjusts folding capacity and degradation (Ron & Walter, 2007). These pathways act together within the proteostasis network to keep protein levels and quality in balance (Balch et al., 2008).

Clinical relevance

Impaired degradation and the accumulation of misfolded proteins are features studied in neurodegenerative and other conditions, and the proteasome is itself a target of pharmacological research. This entry describes the normal mechanisms and their general relevance; it is not a basis for individual diagnosis or treatment.

History

The discovery in the late twentieth century that ubiquitin tagging directs regulated protein degradation, recognised by the 2004 Nobel Prize in Chemistry, established selective proteolysis as a controlled process (Hershko & Ciechanover, 1998). Work on autophagy, recognised by the 2016 Nobel Prize in Physiology or Medicine (Mizushima & Komatsu, 2011), and on the unfolded protein response (Ron & Walter, 2007) extended quality control to bulk degradation and stress signalling, consolidating the modern proteostasis framework.

Key figures

• Aaron Ciechanover
• Avram Hershko
• Irwin Rose
• Cecile Pickart
• Yoshinori Ohsumi
• Peter Walter

Seminal works

• hershko-1998
• mizushima-2011
• balch-2008

Frequently asked questions

What is the difference between the proteasome and autophagy?

The proteasome degrades individual proteins that have been tagged with ubiquitin, whereas autophagy engulfs larger cargo, including aggregates and whole organelles, and delivers it to the lysosome. They are complementary degradation routes.

Why does a cell destroy proteins it has just made?

Removing misfolded, damaged, or no-longer-needed proteins prevents harmful accumulation and lets the cell regulate protein levels in response to its needs, keeping the proteome in balance.