Regulation of Normal and Malignant Hematopoiesis by FBOX Ubiquitin E3 Ligases

• Published in: Trends in immunology 2020-12, Vol.41 (12), p.1128-1140
• Main Authors: Hynes-Smith, R. Willow, Wittorf, Karli J., Buckley, Shannon M.
• Format: Article
• Language: English
• Subjects: Anemia; Apoptosis; Binding sites; Blood diseases; Cell cycle; Cell self-renewal; Cyclin-dependent kinases; F-Box Proteins - metabolism; FBOX proteins; Hematopoiesis; Hematopoiesis - genetics; Hematopoietic Stem Cells; Humans; Kinases; Leukemia; Lymphocytes; Lymphoma; Multiple myeloma; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Proteins; Proteolysis; Stem cells; T cell receptors; Transcription factors; Transportation services; Ubiquitin; Ubiquitin - metabolism; ubiquitin E3 ligases; ubiquitin proteasome system; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - metabolism
• ISSN: 1471-4906; 1471-4981
• DOI: 10.1016/j.it.2020.10.003

Hematopoiesis is responsible for numerous functions, ranging from oxygen transportation to host defense, to injury repair. This process of hematopoiesis is maintained throughout life by hematopoietic stem cells and requires a controlled balance between self-renewal, differentiation, and quiescence. Disrupting this balance can result in hematopoietic malignancies, including anemia, immune deficiency, leukemia, and lymphoma. Recent work has shown that FBOX E3 ligases, a substrate recognition component of the ubiquitin proteasome system (UPS), have an integral role in maintaining this balance. In this review, we detail how FBOX proteins target specific proteins for degradation to regulate hematopoiesis through cell processes, such as cell cycle, development, and apoptosis. Recent work has shown that FBOX proteins have an integral role in maintaining the balance of quiescence, self-renewal, and differentiation of hematopoietic stem and progenitor cells (HSPC) in vertebrates.Altering the activity of certain key FBOX E3 ligases has been correlated with loss of quiescence, aberrant differentiation, and malignant transformation, providing key putative targets for drug discovery.Although FBOX proteins are known to target cell-cycle regulators, new studies demonstrate their ability to regulate other key pathways in hematopoiesis, such as iron homeostasis, signal transduction, transcription, and apoptosis, by targeting specific proteins for degradation.