The ubiquitin ligase Huwe1 regulates the maintenance and lymphoid commitment of hematopoietic stem cells

• Published in: Nature immunology Vol. 17; no. 11; pp. 1312 - 1321
• Main Authors: King, Bryan, Boccalatte, Francesco, Moran-Crusio, Kelly, Wolf, Elmar, Wang, Jingjing, Kayembe, Clarisse, Lazaris, Charalampos, Yu, Xiaofeng, Aranda-Orgilles, Beatriz, Lasorella, Anna, Aifantis, Iannis
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2016; Nature Publishing Group
• Subjects: 13/100; 13/106; 13/31; 13/89; 38/35; 38/39; 38/47; 631/250/232/2058; 631/532/1542; 64/60; Animals; Biomedicine; Bone marrow; Cell Cycle - genetics; Cell Differentiation - genetics; Cell Line; Cell Lineage - genetics; Cell Self Renewal - genetics; Cluster Analysis; Gene Expression Profiling; Genes, myc; Genetic aspects; Genetic regulation; Growth; Hematopoietic stem cells; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Homeostasis; Identification and classification; Immunology; Infectious Diseases; Ligases; Lymphocytes - cytology; Lymphocytes - metabolism; Mice; Mice, Knockout; Mice, Transgenic; Observations; Protein Stability; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Stem cells; Stress, Physiological; Transcription, Genetic; Ubiquitin-Protein Ligases - deficiency; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni.3559

The longevity of hematopoietic stem cells requires strict regulation to prevent their exhaustion. Aifantis and colleagues show that the ubiquitin E3 ligase Huwe1 is needed to suppress the activity of the transcription factor N-myc and maintain the quiescence and function of these cells. Hematopoietic stem cells (HSCs) are dormant in the bone marrow and can be activated in response to diverse stresses to replenish all blood cell types. We identified the ubiquitin ligase Huwe1 as a crucial regulator of HSC function via its post-translational control of the oncoprotein N-myc (encoded by Mycn ). We found Huwe1 to be essential for HSC self-renewal, quiescence and lymphoid-fate specification in mice. Through the use of a fluorescent fusion allele ( Mycn M ), we observed that N-myc expression was restricted to the most immature, multipotent stem and progenitor populations. N-myc expression was upregulated in response to stress or following loss of Huwe1, which led to increased proliferation and stem-cell exhaustion. Mycn depletion reversed most of these phenotypes in vivo , which suggested that the attenuation of N-myc by Huwe1 is essential for reestablishing homeostasis following stress.