E3 ubiquitin ligase Casitas B lineage lymphoma-b and its potential therapeutic implications for immunotherapy

Clin Exp Immunol. 2021 Apr;204(1):14-31. doi: 10.1111/cei.13560. Epub 2021 Jan 10.


The distinction of self from non-self is crucial to prevent autoreactivity and ensure protection from infectious agents and tumors. Maintaining the balance between immunity and tolerance of immune cells is strongly controlled by several sophisticated regulatory mechanisms of the immune system. Among these, the E3 ligase ubiquitin Casitas B cell lymphoma-b (Cbl-b) is a newly identified component in the ubiquitin-dependent protein degradation system, which is thought to be an important negative regulator of immune cells. An update on the current knowledge and new concepts of the relevant immune homeostasis program co-ordinated by Cbl-b in different cell populations could pave the way for future immunomodulatory therapies of various diseases, such as autoimmune and allergic diseases, infections, cancers and other immunopathological conditions. In the present review, the latest findings are comprehensively summarized on the molecular structural basis of Cbl-b and the suppressive signaling mechanisms of Cbl-b in physiological and pathological immune responses, as well as its emerging potential therapeutic implications for immunotherapy in animal models and human diseases.

Keywords: Cbl-b; immunotherapy; ubiquitin-binding protein; ubiquitination.

Publication types

  • Review

MeSH terms

  • Animals
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / metabolism
  • Autoimmune Diseases / therapy*
  • Homeostasis / immunology
  • Humans
  • Hypersensitivity / immunology
  • Hypersensitivity / metabolism
  • Hypersensitivity / therapy*
  • Immune System / cytology
  • Immune System / immunology
  • Immune System / metabolism
  • Immunotherapy / methods*
  • Neoplasms / immunology
  • Neoplasms / metabolism
  • Neoplasms / therapy*
  • Proto-Oncogene Proteins c-cbl / immunology*
  • Proto-Oncogene Proteins c-cbl / metabolism
  • Ubiquitin / immunology
  • Ubiquitin / metabolism


  • Ubiquitin
  • Proto-Oncogene Proteins c-cbl