Sptlc1 is essential for myeloid differentiation and hematopoietic homeostasis

Parthibane, Velayoudame; Acharya, Diwash; Madabushi, Srideshikan Sargur; Myerscough, Dru G.; Abimannan, Thiruvaimozhi; Vijaykrishna, Nagampalli; Blankenberg, Daniel; Bondada, Lavanya; Klarmann, Kimberly D.; Fox, Stephen D.; Andrésson, Þorkell; Tessarollo, Lino; Acharya, Usha; Keller, Jonathan R.; Acharya, Jairaj

doi:10.1182/bloodadvances.2019000729

Cited by 7 publications

(23 citation statements)

References 57 publications

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“…Molecular analysis indicates that aberrant myelopoiesis is accompanied by endoplasmic reticulum stress. These phenotypes are similar to the defects observed in Sptlc1 null mutants ( 30 ). On the other hand, germline null mutants of ssSPTb are homozygous viable and do not show defects in adult hematopoiesis.…”

supporting

confidence: 84%

“…The comparison of the sphingolipid profile between ssSPTa +/+ and ssSPTa −/− described above suggests that SSSPTA plays a major role in the de novo biosynthesis of sphingolipids in the adult hematopoietic system. As with Sptlc1 −/− BMCs, we see a correlation between loss of SSSPTA function, significant decrease in major sphingolipids, and defective myelopoiesis in the BMCs ( 30 ). It is likely that SSSPTA is a critical component of the SPT complex in mammalian adult hematopoietic system.…”

Section: Resultssupporting

confidence: 52%

“…We noticed that ssSPTa −/− embryos begin to degenerate and get absorbed between E6.5 and E7.5. Sptlc1 −/− and Sptlc2 −/− null have also been reported to be early embryonic lethal ( 24 , 30 ). E6.5 embryos were smaller than the corresponding ssSPTa +/+ harvested from the same uterus, indicating disruption of the normal developmental process in the mutant embryos ( Figs.…”

Section: Resultsmentioning

confidence: 99%

“…Extensive analyses in Sptlc1 revealed that loss of SPTLC1 causes myeloid differentiation defects in part because of ER stress and the differentiating BMCs show evidence of unfolded protein response (UPR) ( 30 ). Further, we showed that ER stress in general disrupts myelopoiesis while sparing erythropoiesis.…”

Section: Resultsmentioning

confidence: 99%

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SSSPTA is essential for serine palmitoyltransferase function during development and hematopoiesis

Parthibane

Acharya

Abimannan

et al. 2021

Journal of Biological Chemistry

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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.

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supporting

confidence: 84%

Section: Resultssupporting

confidence: 52%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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SSSPTA is essential for serine palmitoyltransferase function during development and hematopoiesis

Parthibane

Acharya

Abimannan

et al. 2021

Journal of Biological Chemistry

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“…Similarly, disruption of sphingolipid biosynthesis caused by the deletion of SPT long-chain subunit1 (SPTLC)1 or SPTLC2 caused mouse embryonic lethality ( 10 ). Furthermore, it was shown that 1) disruption of de novo sphingolipid synthesis in SPTLC2 heterozygous mice led to bronchial hyperreactivity in the absence of inflammation ( 11 ), 2) inducible deficiency of SPTLC2 in the intestine caused death of mice within ten days upon tamoxifen treatment ( 12 ), and 3) conditional knockout of SPTLC1 subunit in the adult bone marrow affected myeloid differentiation ( 13 ). In contrast, increased sphingolipid levels observed in the brain of ORMDL1 and ORMDL3 double KO (ORMDL1, 3 dKO) mice were linked to the defects in littermate size, disruption of proper myelination, and a neurologic phenotype ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

ORMDL2 Deficiency Potentiates the ORMDL3-Dependent Changes in Mast Cell Signaling

et al. 2021

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The systemic anaphylactic reaction is a life-threatening allergic response initiated by activated mast cells. Sphingolipids are an essential player in the development and attenuation of this response. De novo synthesis of sphingolipids in mammalian cells is inhibited by the family of three ORMDL proteins (ORMDL1, 2, and 3). However, the cell and tissue-specific functions of ORMDL proteins in mast cell signaling are poorly understood. This study aimed to determine cross-talk of ORMDL2 and ORMDL3 proteins in IgE-mediated responses. To this end, we prepared mice with whole-body knockout (KO) of Ormdl2 and/or Ormdl3 genes and studied their role in mast cell-dependent activation events in vitro and in vivo. We found that the absence of ORMDL3 in bone marrow-derived mast cells (BMMCs) increased the levels of cellular sphingolipids. Such an increase was further raised by simultaneous ORMDL2 deficiency, which alone had no effect on sphingolipid levels. Cells with double ORMDL2 and ORMDL3 KO exhibited increased intracellular levels of sphingosine-1-phosphate (S1P). Furthermore, we found that concurrent ORMDL2 and ORMDL3 deficiency increased IκB-α phosphorylation, degranulation, and production of IL-4, IL-6, and TNF-α cytokines in antigen-activated mast cells. Interestingly, the chemotaxis towards antigen was increased in all mutant cell types analyzed. Experiments in vivo showed that passive cutaneous anaphylaxis (PCA), which is initiated by mast cell activation, was increased only in ORMDL2,3 double KO mice, supporting our in vitro observations with mast cells. On the other hand, ORMDL3 KO and ORMDL2,3 double KO mice showed faster recovery from passive systemic anaphylaxis, which could be mediated by increased levels of blood S1P presented in such mice. Our findings demonstrate that Ormdl2 deficiency potentiates the ORMDL3-dependent changes in mast cell signaling.

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E2F2 serves as an essential prognostic biomarker and therapeutic target for human renal cell carcinoma by presenting “E2F2/miR-16–5p/SPTLC1” schema

Yang

Chen

et al. 2023

Translational Oncology

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Sptlc1 is essential for myeloid differentiation and hematopoietic homeostasis

Abstract: Key Points Sptlc1 is essential for myeloid differentiation during hematopoiesis; ER stress prevents myeloid development in Sptlc1 mutant mice. Accumulation of fatty acid promotes ER stress in Sptlc1 mutant myeloid progenitors.

Cited by 7 publications

References 57 publications

SSSPTA is essential for serine palmitoyltransferase function during development and hematopoiesis

SSSPTA is essential for serine palmitoyltransferase function during development and hematopoiesis

ORMDL2 Deficiency Potentiates the ORMDL3-Dependent Changes in Mast Cell Signaling

E2F2 serves as an essential prognostic biomarker and therapeutic target for human renal cell carcinoma by presenting “E2F2/miR-16–5p/SPTLC1” schema

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