Gatekeepers of the Gut: The Roles of Proteasomes at the Gastrointestinal Barrier

Biomolecules. 2021 Jul 5;11(7):989. doi: 10.3390/biom11070989.


The gut epithelial barrier provides the first line of defense protecting the internal milieu from the environment. To circumvent the exposure to constant challenges such as pathogenic infections and commensal bacteria, epithelial and immune cells at the gut barrier require rapid and efficient means to dynamically sense and respond to stimuli. Numerous studies have highlighted the importance of proteolysis in maintaining homeostasis and adapting to the dynamic changes of the conditions in the gut environment. Primarily, proteolytic activities that are involved in immune regulation and inflammation have been examined in the context of the lysosome and inflammasome activation. Yet, the key to cellular and tissue proteostasis is the ubiquitin-proteasome system, which tightly regulates fundamental aspects of inflammatory signaling and protein quality control to provide rapid responses and protect from the accumulation of proteotoxic damage. In this review, we discuss proteasome-dependent regulation of the gut and highlight the pathophysiological consequences of the disarray of proteasomal control in the gut, in the context of aberrant inflammatory disorders and tumorigenesis.

Keywords: auto-immune disease; colitis; colorectal cancer; degradation; gastrointestinal barrier; inflammatory bowel disease; proteostasis; ubiquitin–proteasome system.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Enzyme Activation / immunology
  • Humans
  • Inflammation / enzymology
  • Intestinal Mucosa* / enzymology
  • Intestinal Mucosa* / immunology
  • Lysosomes / enzymology
  • Lysosomes / immunology
  • Proteasome Endopeptidase Complex* / immunology
  • Proteasome Endopeptidase Complex* / metabolism
  • Proteolysis*
  • Signal Transduction / immunology*


  • Proteasome Endopeptidase Complex