CUL-4A stimulates ubiquitylation and degradation of the HOXA9 homeodomain protein.
The HOXA9 homeodomain protein is a key regulator of hematopoiesis and embryonic development. HOXA9 is expressed in primitive hematopoietic cells, and its prompt downregulation is associated with myelocytic maturation. Although transcriptional inactivation of HOXA9 during hematopoietic differentiation has been established, little is known about the biochemical mechanisms underlying the subsequent removal of HOXA9 protein. Here we report that the CUL-4A ubiquitylation machinery controls the stability of HOXA9 by promoting its ubiquitylation and proteasome-dependent degradation. The homeodomain of HOXA9 is responsible for CUL-4A-mediated degradation. Interfering CUL-4A biosynthesis by ectopic expression or by RNA-mediated interference resulted in alterations of the steady-state levels of HOXA9, mirrored by impairment of the ability of 32D myeloid progenitor cells to undergo proper terminal differentiation into granulocytes. These results revealed a novel regulatory mechanism of hematopoiesis by ubiquitin-dependent proteolysis.
Zhang
Yue
Y
Department of Pathology and Laboratory Medicine, Weill Medical College and Graduate School of Medical Sciences of Cornell University, 1300 York Avenue, New York, NY 10021, USA.
Morrone
Giovanni
G
Zhang
Jianxuan
J
Chen
Xiaoai
X
Lu
Xiaoling
X
Ma
Liang
L
Moore
Malcolm
M
Zhou
Pengbo
P
D002454:Cell Differentiation / Q000502:physiology; D044842:Cullin Proteins / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D042381:Granulocyte Precursor Cells / Q000502:physiology; D006410:Hematopoiesis / Q000502:physiology; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D009097:Multienzyme Complexes / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000378:metabolism*
C114234:CUL4A protein, human; D044842:Cullin Proteins; D018398:Homeodomain Proteins; D009097:Multienzyme Complexes; D025801:Ubiquitin; C097899:homeobox protein HOXA9; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex