Proteasome-derived peptides: separating the trash from the recycling

Trends Biochem Sci. 2025 Sep;50(9):779-794. doi: 10.1016/j.tibs.2025.06.007. Epub 2025 Jul 12.

Abstract

The proteasome is an essential protein complex in all cells. Proteasomes have two main functions: protein degradation and peptide generation. While proteasome-dependent protein degradation removes proteins and is critical for cellular function, the newly generated proteasome-derived peptides, which range in size and sequence, are emerging as essential cellular effector molecules: they are expressed on MHC-I in the immune system, function as novel modulators of neuronal signaling, are involved in innate immunity and intracellular signaling, and can be metabolized further for important cellular processes. Here, we take a comprehensive look at the mechanics behind proteasome-mediated peptide generation; the function of proteasome-derived peptides in signaling and metabolism relevant to cellular biology, health, and disease; and the techniques enabling these studies.

Keywords: amino acid recycling; antimicrobial peptides; immunoproteasome; neuronal membrane proteasome; peptides; proteasome-derived peptides.

Publication types

  • Review

MeSH terms

  • Animals
  • Humans
  • Peptides* / chemistry
  • Peptides* / metabolism
  • Proteasome Endopeptidase Complex* / metabolism
  • Proteolysis
  • Signal Transduction

Substances

  • Proteasome Endopeptidase Complex
  • Peptides