Sphingomyelin synthase related protein is a mammalian phosphatidylethanolamine phospholipase C

PLIC-1, a newly described ubiquitin-related protein, inhibited both Jurkat migration toward SDF-1α and A431 wound healing, but the closely related PLIC-2 did not. PLIC-1 prevented the SDF-1α–induced activation of phospholipase C, decreased ligand-induced internalization of SDF-1α receptor CXCR4 and inhibited chemotaxis signaled by a transfected Gi-coupled receptor. However, PLIC-1 had no effect on Gs-mediated adenylyl cyclase activation, and inhibited only the Gβγ-dependent component of Gq-initiated increase in [Ca2+]i, which is consistent with selective inhibition of Gβγ function. PLIC-1 colocalized with G proteins in lamellae and pseudopods, and precipitated Gβγ in pull downs. Interaction with Gβγ did not require PLIC-1's ubiquitin-like or ubiquitin-associated domains, and proteasome inhibition had no effect on SDF-1α activation of phospholipase C, indicating that PLIC-1's inhibition of Gβγ did not result from effects on proteasome function. Thus, PLIC-1 inhibits Gi signaling by direct association with Gβγ; because it also interacts with CD47, a modulator of integrin function, it likely has a role integrating adhesion and signaling components of cell migration.

Download Full-text

Diacylglycerol kinase δ and sphingomyelin synthase–related protein functionally interact via their sterile α motif domains

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.012369 ◽

2020 ◽

Vol 295 (10) ◽

pp. 2932-2947 ◽

Cited By ~ 6

Author(s):

Chiaki Murakami ◽

Fumi Hoshino ◽

Hiromichi Sakai ◽

Yasuhiro Hayashi ◽

Atsushi Yamashita ◽

...

Keyword(s):

Molecular Species ◽

Functional Outcomes ◽

Palmitoleic Acid ◽

Diacylglycerol Kinase ◽

Full Length ◽

Related Protein ◽

Sphingomyelin Synthase ◽

Phosphatidylinositol Turnover ◽

The Relationship

The δ isozyme of diacylglycerol kinase (DGKδ) plays critical roles in lipid signaling by converting diacylglycerol (DG) to phosphatidic acid (PA). We previously demonstrated that DGKδ preferably phosphorylates palmitic acid (16:0)- and/or palmitoleic acid (16:1)-containing DG molecular species, but not arachidonic acid (20:4)-containing DG species, which are recognized as DGK substrates derived from phosphatidylinositol turnover, in high glucose-stimulated myoblasts. However, little is known about the origin of these DG molecular species. DGKδ and two DG-generating enzymes, sphingomyelin synthase (SMS) 1 and SMS-related protein (SMSr), contain a sterile α motif domain (SAMD). In this study, we found that SMSr–SAMD, but not SMS1–SAMD, co-immunoprecipitates with DGKδ–SAMD. Full-length DGKδ co-precipitated with full-length SMSr more strongly than with SMS1. However, SAMD-deleted variants of SMSr and DGKδ interacted only weakly with full-length DGKδ and SMSr, respectively. These results strongly suggested that DGKδ interacts with SMSr through their respective SAMDs. To determine the functional outcomes of the relationship between DGKδ and SMSr, we used LC-MS/MS to investigate whether overexpression of DGKδ and/or SMSr in COS-7 cells alters the levels of PA species. We found that SMSr overexpression significantly enhances the production of 16:0- or 16:1-containing PA species such as 14:0/16:0-, 16:0/16:0-, 16:0/18:1-, and/or 16:1/18:1-PA in DGKδ-overexpressing COS-7 cells. Moreover, SMSr enhanced DGKδ activity via their SAMDs in vitro. Taken together, these results strongly suggest that SMSr is a candidate DG-providing enzyme upstream of DGKδ and that the two enzymes represent a new pathway independent of phosphatidylinositol turnover.

Download Full-text

Mutations in the Second Cytoplasmic Loop of the Rat Parathyroid Hormone (PTH)/PTH-related Protein Receptor Result in Selective Loss of PTH-stimulated Phospholipase C Activity

Journal of Biological Chemistry ◽

10.1074/jbc.272.11.6882 ◽

1997 ◽

Vol 272 (11) ◽

pp. 6882-6889 ◽

Cited By ~ 91

Author(s):

Akiko Iida-Klein ◽

Jun Guo ◽

Masahiko Takemura ◽

Matthew T. Drake ◽

John T. Potts ◽

...

Keyword(s):

Parathyroid Hormone ◽

Phospholipase C ◽

Related Protein ◽

Cytoplasmic Loop ◽

Selective Loss ◽

Protein Receptor

Download Full-text

Sphingomyelin synthase-related protein SMSr controls ceramide homeostasis in the ER

The Journal of Cell Biology ◽

10.1083/jcb.200903152 ◽

2009 ◽

Vol 185 (6) ◽

pp. 1013-1027 ◽

Cited By ~ 96

Author(s):

Ana M. Vacaru ◽

Fikadu G. Tafesse ◽

Philipp Ternes ◽

Vangelis Kondylis ◽

Martin Hermansson ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Secretory Pathway ◽

Sphingolipid Metabolism ◽

Related Protein ◽

Sphingomyelin Synthase ◽

Transfer Protein ◽

Early Secretory Pathway ◽

Cell Organization ◽

Ceramide Accumulation ◽

Substantial Rise

Ceramides are central intermediates of sphingolipid metabolism with critical functions in cell organization and survival. They are synthesized on the cytosolic surface of the endoplasmic reticulum (ER) and transported by ceramide transfer protein to the Golgi for conversion to sphingomyelin (SM) by SM synthase SMS1. In this study, we report the identification of an SMS1-related (SMSr) enzyme, which catalyses the synthesis of the SM analogue ceramide phosphoethanolamine (CPE) in the ER lumen. Strikingly, SMSr produces only trace amounts of CPE, i.e., 300-fold less than SMS1-derived SM. Nevertheless, blocking its catalytic activity causes a substantial rise in ER ceramide levels and a structural collapse of the early secretory pathway. We find that the latter phenotype is not caused by depletion of CPE but rather a consequence of ceramide accumulation in the ER. Our results establish SMSr as a key regulator of ceramide homeostasis that seems to operate as a sensor rather than a converter of ceramides in the ER.

Download Full-text

Nuclear Phosphatidylcholine and Sphingomyelin Metabolism of Thyroid Cells Changes during Stratospheric Balloon Flight

Journal of Biomedicine and Biotechnology ◽

10.1155/2009/125412 ◽

2009 ◽

Vol 2009 ◽

pp. 1-5 ◽

Cited By ~ 4

Author(s):

Elisabetta Albi ◽

Samuela Cataldi ◽

Maristella Villani ◽

Giuseppina Perrella

Keyword(s):

Phospholipase C ◽

Radiation Treatment ◽

Physiological State ◽

Free Fraction ◽

Thyroid Cells ◽

Neutral Sphingomyelinase ◽

Sphingomyelin Synthase ◽

Quiescent Cells ◽

Stratospheric Balloon

Nuclear sphingomyelin and phosphatidylcholine metabolism is involved in the response to ultraviolet radiation treatment in different ways related to the physiological state of cells. To evaluate the effects of low levels of radiation from the stratosphere on thyroid cells, proliferating and quiescent FRTL-5 cells were flown in a stratospheric balloon (BIRBA mission). After recovery, the activity of neutral sphingomyelinase, phosphatidylcholine-specific phospholipase C, sphingomyelin synthase, and reverse sphingomyelin synthase was assayed in purified nuclei and the nuclei-free fraction. In proliferating FRTL-5, space radiation stimulate nuclear neutral sphingomyelinase and reverse sphingomyelin synthase activity, whereas phosphatidylcholine-specific phospholipase C and sphingomyelin synthase were inhibited, thus inducing sphingomyelin degradation and phosphatidylcholine synthesis. This effect was lower in quiescent cells. The possible role of nuclear lipid metabolism in the thyroid damage induced by space radiations is discussed.

Download Full-text

Phosphatidylcholine/sphingomyelin metabolism crosstalk inside the nucleus

Biochemical Journal ◽

10.1042/bj20070758 ◽

2008 ◽

Vol 410 (2) ◽

pp. 381-389 ◽

Cited By ~ 31

Author(s):

Elisabetta Albi ◽

Remo Lazzarini ◽

Mariapia Viola Magni

Keyword(s):

Cell Proliferation ◽

Lipid Metabolism ◽

Phospholipase C ◽

Nuclear Membrane ◽

Enzyme Activities ◽

Cell Function ◽

Minor Component ◽

Neutral Sphingomyelinase ◽

Sphingomyelin Synthase

It is known that phospholipids represent a minor component of chromatin. It has been highlighted recently that these lipids are metabolized directly inside the nucleus, thanks to the presence of enzymes related to their metabolism, such as neutral sphingomyelinase, sphingomyelin synthase, reverse sphingomyelin synthase and phosphatidylcholine-specific phospholipase C. The chromatin enzymatic activities change during cell proliferation, differentiation and/or apoptosis, independently from the enzyme activities present in nuclear membrane, microsomes or cell membranes. This present study aimed to investigate crosstalk in lipid metabolism in nuclear membrane and chromatin isolated from rat liver in vitro and in vivo. The effect of neutral sphingomyelinase activity on phosphatidylcholine-specific phospholipase C and sphingomyelin synthase, which enrich the intranuclear diacylglycerol pool, and the effect of phosphatidylcholine-specific phospholipase C activity on neutral sphingomyelinase and reverse sphingomyelin synthase, which enrich the intranuclear ceramide pool, was investigated. The results show that in chromatin, there exists a phosphatidylcholine/sphingomyelin metabolism crosstalk which regulates the intranuclear ceramide/diacylglycerol pool. The enzyme activities were inhibited by D609, which demonstrated the specificity of this crosstalk. Chromatin lipid metabolism is activated in vivo during cell proliferation, indicating that it could play a role in cell function. The possible mechanism of crosstalk is discussed here, with consideration to recent advances in the field.

Download Full-text