SSSPTA is essential for serine palmitoyltransferase function during development and hematopoiesis
| Autor: | Ferri Soheilian, Velayoudame Parthibane, Lino Tessarollo, Kunio Nagashima, Stephen D. Fox, Jonathan R. Keller, Usha Acharya, Diwash Acharya, Jairaj K. Acharya, Thiruvaimozhi Abimannan, Thorkell Andresson, Jing Lin, Sargur Madabushi Srideshikan, Acong Yang, Kimberly D. Klarmann |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
GMP granulocyte-macrophage precursor Myeloid ssSPTa ssSPTb CMP common myeloid precursor Serine C-Palmitoyltransferase Biochemistry Substrate Specificity serine palmitoyltransferase Mice UPR unfolded protein response LCB long-chain base Catalytic Domain MEP megakaryocyte-erythrocyte precursor LT-HSCs long-term hematopoietic stem cells Mice Knockout granulopoiesis Chemistry LK Lin− c-Kit+ Sca1− LSK Lin−c-Kit+ Sca1+ Cell Differentiation Null allele Cell biology GM-CSF granulocyte macrophage colony stimulating factor medicine.anatomical_structure ST-HSCs short-term hematopoietic stem cells Myelopoiesis ER stress Research Article Protein subunit BMCs bone marrow cells Bone Marrow Cells myelopoiesis PLP pyridoxal phosphate 03 medical and health sciences EBs embryoid bodies medicine Animals Progenitor cell SPTLC1 MPP multipotent progenitor cell Molecular Biology Sphingolipids 030102 biochemistry & molecular biology Serine C-palmitoyltransferase HSCs hematopoietic stem cells Cell Biology SPT serine palmitoyltransferase hematopoiesis hematopoietic stem cells Mice Inbred C57BL 030104 developmental biology Bone marrow Acyl Coenzyme A sphingolipid IL-3 interleukin |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X |
| Popis: | Serine palmitoyltransferase complex (SPT) mediates the first and rate-limiting step in the de novo sphingolipid biosynthetic pathway. The larger subunits SPTLC1 and SPTLC2/SPTLC3 together form the catalytic core while a smaller third subunit either SSSPTA or SSSPTB has been shown to increase the catalytic efficiency and provide substrate specificity for the fatty acyl-CoA substrates. The in vivo biological significance of these smaller subunits in mammals is still unknown. Here, using two null mutants, a conditional null for ssSPTa and a null mutant for ssSPTb, we show that SSSPTA is essential for embryogenesis and mediates much of the known functions of the SPT complex in mammalian hematopoiesis. The ssSPTa null mutants are embryonic lethal at E6.5 much like the Sptlc1 and Sptlc2 null alleles. Mx1-Cre induced deletion of ssSPTa leads to lethality and myelopoietic defect. Chimeric and competitive bone marrow transplantation experiments show that the defect in myelopoiesis is accompanied by an expansion of the Lin−Sca1+c-Kit+ stem and progenitor compartment. Progenitor cells that fail to differentiate along the myeloid lineage display evidence of endoplasmic reticulum stress. On the other hand, ssSPTb null mice are homozygous viable, and analyses of the bone marrow cells show no significant difference in the proliferation and differentiation of the adult hematopoietic compartment. SPTLC1 is an obligatory subunit for the SPT function, and because Sptlc1−/− and ssSPTa−/− mice display similar defects during development and hematopoiesis, we conclude that an SPT complex that includes SSSPTA mediates much of its developmental and hematopoietic functions in a mammalian model. |
| Databáze: | OpenAIRE |
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