UMMS Affiliation

Department of Molecular, Cell and Cancer Biology

Publication Date

2019-11-26

Document Type

Article

Disciplines

Cancer Biology | Cell Biology | Cellular and Molecular Physiology

Abstract

Serine palmitoyltransferase (SPT) long-chain base subunit 1 (SPTLC1) is 1 of the 2 main catalytic subunits of the SPT complex, which catalyzes the first and rate-limiting step of sphingolipid biosynthesis. Here, we show that Sptlc1 deletion in adult bone marrow (BM) cells results in defective myeloid differentiation. In chimeric mice from noncompetitive BM transplant assays, there was an expansion of the Lin- c-Kit+ Sca-1+ compartment due to increased multipotent progenitor production, but myeloid differentiation was severely compromised. We also show that defective biogenesis of sphingolipids in the endoplasmic reticulum (ER) leads to ER stress that affects myeloid differentiation. Furthermore, we demonstrate that transient accumulation of fatty acid, a substrate for sphingolipid biosynthesis, could be partially responsible for the ER stress. Independently, we find that ER stress in general, such as that induced by the chemical thapsigargin or the fatty acid palmitic acid, compromises myeloid differentiation in culture. These results identify perturbed sphingolipid metabolism as a source of ER stress, which may produce diverse pathological effects related to differential cell-type sensitivity.

Keywords

Hematopoiesis and Stem Cells, Phagocytes, Granulocytes, and Myelopoiesis, chimera organism, emergency service, hospital, fatty acids, homeostasis, mice, palmitic acid, proto-oncogene protein c-kit, serine, sphingolipids, stress

Rights and Permissions

Copyright The American Society of Hematology. Publisher PDF posted as allowed by the publisher's copyright and author rights information at https://ashpublications.org/bloodadvances/pages/copyright.

DOI of Published Version

10.1182/bloodadvances.2019000729

Source

Blood Adv. 2019 Nov 26;3(22):3635-3649. doi: 10.1182/bloodadvances.2019000729. Link to article on publisher's site

Journal/Book/Conference Title

Blood advances

Comments

Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to Article in PubMed

PubMed ID

31751474

Download

Share

COinS