sphingomyelin synthase
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2021 ◽  
Author(s):  
Melanie C. Ridgway ◽  
Daniela Cihalova ◽  
Simon H.J. Brown ◽  
Phuong Tran ◽  
Todd W. Mitchell ◽  
...  

Male and female Plasmodium falciparum gametocytes are the parasite lifecycle stage responsible for transmission of malaria from the human host to mosquito vector. Not only are gametocytes able to survive in radically different host environments, but they are also precursors for male and female gametes that reproduce sexually soon after ingestion by the mosquito. Here we investigate the sex-specific lipid metabolism of gametocytes within their host red blood cell. Comparison of the male and female lipidome identifies cholesteryl esters and dihydrosphingomyelin enrichment in female gametocytes. Chemical inhibition of each of these lipid types in mature gametocytes suggests dihydrosphingomyelin synthesis but not cholesteryl ester synthesis is important for gametocyte viability. Genetic disruption of each of the two sphingomyelin synthase gene points towards sphingomyelin synthesis contributing to gametocytogenesis. This study shows that gametocytes are distinct from asexual stages, and that the lipid composition is also vastly different between male and female gametocytes, reflecting the different cellular roles these stages play. Together our results highlight the sex-specific nature of gametocyte lipid metabolism that has the potential to be targeted to block malaria transmission.


2021 ◽  
Author(s):  
Melanie C. Ridgway ◽  
Daniela Cihalova ◽  
Simon H. J. Brown ◽  
Phuong Tran ◽  
Todd W. Mitchell ◽  
...  

Male and female Plasmodium falciparum gametocytes are the parasite lifecycle stage responsible for transmission of malaria from the human host to mosquito vector. Not only are gametocytes able to survive in radically different host environments, but they are also precursors for male and female gametes that reproduce sexually soon after ingestion by the mosquito. Here we investigate the sex-specific lipid metabolism of gametocytes within their host red blood cell and poised for ingestion by the mosquito vector and subsequent sexual reproduction. Comparison of the male and female lipidome identifies cholesteryl esters and dihydrosphingomyelin enrichment in female gametocytes. Chemical inhibition of each of these lipid types in mature gametocytes suggests dihydrosphingomyelin synthesis but not cholesteryl ester synthesis is important for sex-specific gametocyte viability. Genetic disruption of each of the two sphingomyelin synthase gene points towards sphingomyelin synthesis contributing to gametocytogenesis. This study shows that gametocytes are not only distinct from asexual stages, but that the lipid composition is also vastly different between male and female gametocytes, reflecting the different cellular roles these stages play. Together our results highlight the sex-specific nature of gametocyte lipid metabolism that has the potential to be targeted to block malaria transmission.


iScience ◽  
2021 ◽  
pp. 103449
Author(s):  
Zhiqiang Li ◽  
Yeun-po Chiang ◽  
Mulin He ◽  
Tilla S. Worgall ◽  
Hongwen Zhou ◽  
...  

2021 ◽  
Vol 5 (20) ◽  
pp. 4265-4277
Author(s):  
Yoritaka Fujii ◽  
Makoto Taniguchi ◽  
Shingo Nagaya ◽  
Yoshibumi Ueda ◽  
Chieko Hashizume ◽  
...  

Abstract Sphingomyelin synthase 1 (SMS1) contributes to the generation of membrane sphingomyelin (SM) and affects SM-mediated physiological functions. Here, we describe the hematologic phenotypes, such as reduced circulating platelets and dysfunctional hemostasis, in SMS1-deficient (SMS1-KO) mice. SMS1-KO mice display pathologic manifestations related to idiopathic thrombocytopenia (ITP), including relatively high amounts of peripheral blood reticulated platelets, enhanced megakaryopoiesis in the bone marrow and spleen, and splenomegaly. Deficiency of SMS1, but not SMS2, prevented SM production and enhanced phosphatidylserine (PS) externalization on the plasma membranes of platelets and megakaryocytes. Consequently, SMS1-KO platelets were excessively cleared by macrophages in the spleen. Multimer formation in the plasma membrane of TMEM16F, a known calcium (Ca2+)-activated nonselective ion channel and Ca2+-dependent PS scramblase, was enhanced; the result was PS externalization to outer leaflets through increased Ca2+ influx in immortalized mouse embryonic fibroblasts established from SMS1-KO mice (SMS1-KO tMEFs), as seen with SMS1-KO platelets. Thus, SMS1 deficiency changed the TMEM16F distribution on the membrane microdomain, regulating Ca2+ influx-dependent PS exposure. SMS1-KO tMEFs in which TMEM16F was knocked out by using the CRISPR/Cas9 system lacked both the Ca2+ influx and excess PS exposure seen in SMS1-KO tMEFs. Therefore, SM depletion on platelet membrane microdomains due to SMS1 deficiency enhanced PS externalization via a Ca2+ influx through TMEM16F activation, leading to elevated platelet clearance and causing hemostasis dysfunction through thrombocytopenia. Our current findings show that the SM-rich microdomain generated by SMS1 is a potent regulator of thrombocytopenia through TMEM16F, suggesting that its dysfunction may be a novel additional mechanism of ITP.


Membranes ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 787
Author(s):  
Lucia Sessa ◽  
Anna Maria Nardiello ◽  
Jacopo Santoro ◽  
Simona Concilio ◽  
Stefano Piotto

Sphingolipids are a class of lipids acting as key modulators of many physiological and pathophysiological processes. Hydroxylation patterns have a major influence on the biophysical properties of sphingolipids. In this work, we have studied the mechanism of action of hydroxylated lipids in sphingomyelin synthase (SMS). The structures of the two human isoforms, SMS1 and SMS2, have been generated through neural network supported homology. Furthermore, we have elucidated the reaction mechanism that allows SMS to recover the choline head from a phosphocholine (PC) and transfer it to ceramide, and we have clarified the role of the hydroxyl group in the interaction with the enzyme. Finally, the effect of partial inhibition of SMS on the levels of PC and sphingomyelin was calculated for different rate constants solving ordinary differential equation systems.


Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1574
Author(s):  
Julia E. Hölper ◽  
Finn Grey ◽  
John Kenneth Baillie ◽  
Tim Regan ◽  
Nicholas J. Parkinson ◽  
...  

Herpesviruses are large DNA viruses, which encode up to 300 different proteins including enzymes enabling efficient replication. Nevertheless, they depend on a multitude of host cell proteins for successful propagation. To uncover cellular host factors important for replication of pseudorabies virus (PrV), an alphaherpesvirus of swine, we performed an unbiased genome-wide CRISPR/Cas9 forward screen. To this end, a porcine CRISPR-knockout sgRNA library (SsCRISPRko.v1) targeting 20,598 genes was generated and used to transduce porcine kidney cells. Cells were then infected with either wildtype PrV (PrV-Ka) or a PrV mutant (PrV-gD–Pass) lacking the receptor-binding protein gD, which regained infectivity after serial passaging in cell culture. While no cells survived infection with PrV-Ka, resistant cell colonies were observed after infection with PrV-gD–Pass. In these cells, sphingomyelin synthase 1 (SMS1) was identified as the top hit candidate. Infection efficiency was reduced by up to 90% for PrV-gD–Pass in rabbit RK13-sgms1KO cells compared to wildtype cells accompanied by lower viral progeny titers. Exogenous expression of SMS1 partly reverted the entry defect of PrV-gD–Pass. In contrast, infectivity of PrV-Ka was reduced by 50% on the knockout cells, which could not be restored by exogenous expression of SMS1. These data suggest that SMS1 plays a pivotal role for PrV infection, when the gD-mediated entry pathway is blocked.


2021 ◽  
Vol 22 (14) ◽  
pp. 7270
Author(s):  
Tereza Daňhelovská ◽  
Lucie Zdražilová ◽  
Hana Štufková ◽  
Marie Vanišová ◽  
Nikol Volfová ◽  
...  

The Acyl-CoA-binding domain-containing protein (ACBD3) plays multiple roles across the cell. Although generally associated with the Golgi apparatus, it operates also in mitochondria. In steroidogenic cells, ACBD3 is an important part of a multiprotein complex transporting cholesterol into mitochondria. Balance in mitochondrial cholesterol is essential for proper mitochondrial protein biosynthesis, among others. We generated ACBD3 knock-out (ACBD3-KO) HEK293 and HeLa cells and characterized the impact of protein absence on mitochondria, Golgi, and lipid profile. In ACBD3-KO cells, cholesterol level and mitochondrial structure and functions are not altered, demonstrating that an alternative pathway of cholesterol transport into mitochondria exists. However, ACBD3-KO cells exhibit enlarged Golgi area with absence of stacks and ribbon-like formation, confirming the importance of ACBD3 in Golgi stacking. The glycosylation of the LAMP2 glycoprotein was not affected by the altered Golgi structure. Moreover, decreased sphingomyelins together with normal ceramides and sphingomyelin synthase activity reveal the importance of ACBD3 in ceramide transport from ER to Golgi.


2021 ◽  
Vol 35 (S1) ◽  
Author(s):  
Chiaki Murakami ◽  
Masataka Furuta ◽  
Yuki Numagami ◽  
Fumio Sakane

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