Hematopoietic cells from Ube1L-deficient mice exhibit an impaired proliferation defect under the stress of bone marrow transplantation.
Following bone marrow transplantation, donor stem cells are recruited from their quiescent status to promote the rapid reconstitution in recipients. This dynamic process is tightly regulated by a complex of internal and external signals. Protein modification by the ubiquitin like modifier ISG15 (ISGylation) is strongly induced by type I interferons (IFNs). There are higher levels of type I IFNs and protein ISGylation in the bone marrow of recipients shortly after transplantation. In order to clarify the physiological function of protein ISGylation, we generated a mouse model that lacks protein ISGylation due to deficiency of ISG15 conjugating enzyme Ube1L (Ube1L(-/-)). In this report, we focused on the analysis of the hematopoietic system in Ube1L(-)(/)(-) mice in steady-state hematopoiesis and its potential protective role during bone marrow reconstitution. Here we demonstrated that In Ube1L(-/-) mice, steady-state hematopoiesis was unperturbed. However, transplantation experiment revealed a 50% reduction in repopulation potential of Ube1L-deficient cells at 3weeks posttransplantation, but no differences at 6 and 12weeks. A competitive transplantation experiment magnified and extended this phenotype. Cell cycle analysis revealed that under the condition with high levels of IFNs and protein ISGylation, the Ube1L deficiency can cause G2/M phase block of cell cycle in hematopoietic multipotential progenitors. These observations indicate that although protein ISGylation is dispensable for steady-state hematopoiesis, it plays a significant role during interferon related stress response, such as bone marrow transplantation.
Cong
Xiuli
X
Moores UCSD Cancer Center, University of California San Diego, La Jolla, 92093, USA.
Yan
Ming
M
Yin
Xiaoyan
X
Zhang
Dong-Er
DE
D000818:Animals; D016026:Bone Marrow Transplantation; D002453:Cell Cycle; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism*; D006410:Hematopoiesis / Q000235:genetics*; D007370:Interferon Type I / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D044764:Ubiquitin-Activating Enzymes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism
D016207:Cytokines; C489550:G1p2 protein, mouse; D007370:Interferon Type I; D014452:Ubiquitins; D007371:Interferon-gamma; D044764:Ubiquitin-Activating Enzymes