Ubiquitination and proteasomal degradation of proteins

Lysosomal and Proteasomal Protein Degradation in the Cell

Ubiquitination of Proteins

Life in the cell is not just about building—it’s about renewing. Proteins must be made when needed and removed when they’re faulty, old, or simply in the way. Two main systems handle this essential cleanup:

The lysosome
The proteasome

Each evolved to clean up with surgical precision or bulk digestion.

Lysosomal Degradation

The lysosome is a membrane-bound organelle packed with hydrolytic enzymes that digest:

Proteins
Nucleic acids
Lipids
Even entire organelles

Think of it as the cell’s recycling center.

Process:

Damaged or unneeded parts of the cell are wrapped into an autophagosome
The autophagosome fuses with the lysosome
Lysosomal enzymes digest contents into reusable building blocks

This process is called autophagy and becomes crucial during:

Cellular stress
Starvation
Organelle turnover

Lysosomes work non-selectively: they digest whatever they're given.

Proteasomal Degradation

The proteasome targets individual proteins, not whole structures. But it needs a signal: ubiquitin.

Ubiquitination Process:

E1 (activating enzyme) primes the ubiquitin molecule
E2 (conjugating enzyme) carries it
E3 (ligase) attaches it to the target protein

A polyubiquitin chain (often linked at lysine-48) serves as a "destroy me" label.

Once tagged, the protein is:

Recognized by the 26S proteasome
Unfolded and fed into its catalytic core
Broken into small peptides for recycling

Why Does This Matter?

Without these systems:

Cells would accumulate damaged proteins
Neurotoxic aggregates would form (as in Parkinson’s or Alzheimer’s)
The cell couldn't rapidly regulate key processes (e.g. cell cycle, inflammation)

These systems allow cells to maintain proteostasis—a balance between synthesis and degradation. The elegance lies not just in efficiency, but in selective control.

References

Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell. 2011;147(4):728–741. https://doi.org/10.1016/j.cell.2011.10.026
Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem. 1998;67:425–479. https://doi.org/10.1146/annurev.biochem.67.1.425