Document Detail

Lamin B receptor regulates the growth and maturation of myeloid progenitors via its sterol reductase domain: implications for cholesterol biosynthesis in regulating myelopoiesis.
MedLine Citation:
PMID:  22140257     Owner:  NLM     Status:  MEDLINE    
Lamin B receptor (LBR) is a bifunctional nuclear membrane protein with N-terminal lamin B and chromatin-binding domains plus a C-terminal sterol Δ(14) reductase domain. LBR expression increases during neutrophil differentiation, and deficient expression disrupts neutrophil nuclear lobulation characteristic of Pelger-Huët anomaly. Thus, LBR plays a critical role in regulating myeloid differentiation, but how the two functional domains of LBR support this role is currently unclear. We previously identified abnormal proliferation and deficient functional maturation of promyelocytes (erythroid, myeloid, and lymphoid [EML]-derived promyelocytes) derived from EML-ic/ic cells, a myeloid model of ichthyosis (ic) bone marrow that lacks Lbr expression. In this study, we provide new evidence that cholesterol biosynthesis is important to myeloid cell growth and is supported by the sterol reductase domain of Lbr. Cholesterol biosynthesis inhibitors caused growth inhibition of EML cells that increased in EML-derived promyelocytes, whereas cells lacking Lbr exhibited complete growth arrest at both stages. Lipid production increased during wild-type neutrophil maturation, but ic/ic cells exhibited deficient levels of lipid and cholesterol production. Ectopic expression of a full-length Lbr in EML-ic/ic cells rescued both nuclear lobulation and growth arrest in cholesterol starvation conditions. Lipid production also was rescued, and a deficient respiratory burst was corrected. Expression of just the C-terminal sterol reductase domain of Lbr in ic/ic cells also improved each of these phenotypes. Our data support the conclusion that the sterol Δ(14) reductase domain of LBR plays a critical role in cholesterol biosynthesis and that this process is essential to both myeloid cell growth and functional maturation.
Gayathri Subramanian; Pulkit Chaudhury; Krishnakumar Malu; Samantha Fowler; Rahul Manmode; Deepali Gotur; Monika Zwerger; David Ryan; Rita Roberti; Peter Gaines
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-12-02
Journal Detail:
Title:  Journal of immunology (Baltimore, Md. : 1950)     Volume:  188     ISSN:  1550-6606     ISO Abbreviation:  J. Immunol.     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2011-12-21     Completed Date:  2012-02-16     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  2985117R     Medline TA:  J Immunol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  85-102     Citation Subset:  AIM; IM    
Department of Biological Sciences, University of Massachusetts, Lowell, MA 01854, USA.
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MeSH Terms
Bone Marrow Cells / cytology,  immunology,  metabolism
Cell Line
Cholesterol / biosynthesis,  genetics,  immunology*
Lipid Metabolism / genetics,  immunology*
Myeloid Progenitor Cells / cytology,  immunology*,  metabolism
Myelopoiesis / genetics,  immunology*
Protein Structure, Tertiary
Receptors, Cytoplasmic and Nuclear / genetics,  immunology*,  metabolism
Grant Support
Reg. No./Substance:
0/Receptors, Cytoplasmic and Nuclear; 0/lamin B receptor; 57-88-5/Cholesterol

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