title: Lamin B receptor regulates the growth and maturation of myeloid progenitors via its sterol reductase domain: implications for cholesterol biosynthesis in regulating myelopoiesis.
abstract: 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.
authors.affiliation: Department of Biological Sciences, University of Massachusetts, Lowell, MA 01854, USA.
authors.forename: Gayathri
authors.initials: G
authors.lastname: Subramanian
authors.forename: Pulkit
authors.initials: P
authors.lastname: Chaudhury
authors.forename: Krishnakumar
authors.initials: K
authors.lastname: Malu
authors.forename: Samantha
authors.initials: S
authors.lastname: Fowler
authors.forename: Rahul
authors.initials: R
authors.lastname: Manmode
authors.forename: Deepali
authors.initials: D
authors.lastname: Gotur
authors.forename: Monika
authors.initials: M
authors.lastname: Zwerger
authors.forename: David
authors.initials: D
authors.lastname: Ryan
authors.forename: Rita
authors.initials: R
authors.lastname: Roberti
authors.forename: Peter
authors.initials: P
authors.lastname: Gaines
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D002784:Cholesterol / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D050356:Lipid Metabolism / Q000235:genetics / Q000276:immunology*; D051379:Mice; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D038042:Myelopoiesis / Q000235:genetics / Q000276:immunology*; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000097682:Lamin B Receptor
chemical_list: D002784:Cholesterol; D018160:Receptors, Cytoplasmic and Nuclear; D000097682:Lamin B Receptor