Better degradation for better preservation

In every living cell, misfolded, dislocated, and dysfunctional proteins are directed to degradation pathways, to prevent their harmful buildup and recycle their basic components. The primary mechanism for protein degradation involves ubiquitylation, whereby an E3 ligase enzyme attaches a ubiquitin molecule to the target protein. This process relies on recognizing specific short sequences, called degrons, within the protein. Once tagged, the protein is sent to the proteasome for degradation and recycling. Maintaining ubiquitylation-based degradation is essential for cellular health, and nearly 5% of mammalian genes are dedicated to this function, though the full complexity of proteostasis remains elusive. In a recent article in the Journal of Cell Biology, Dr. Itay Koren and colleagues explore a quality control system for mislocalized secretory proteins. They highlight the cooperative role of E3 ligases and dipeptidyl peptidases 8 and 9, which initiate cleavage of ubiquitin-tagged proteins, enhancing this quality control pathway.