Exploring the Therapeutic Landscape of Sphingomyelinases

Shanbhogue, Prajna; Hannun, Yusuf A.

doi:10.1007/164_2018_179

Cited by 17 publications

(12 citation statements)

References 140 publications

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“…Combing of I. scapularis genome showed the presence of several other sphingomyelinases that are currently addressed in tick-LGTV interactions and exosome-mediated transmission of flaviviruses. In all animals, plants, and fungi, and in some of the prokaryotes and viruses, sphingolipids are the ubiquitous constituents of all the membranes, which include plasma membranes and membranebound organelles (Raposo and Stoorvogel, 2013;Schneider-Schaulies and Schneider-Schaulies, 2015;Bezgovsek et al, 2018;Shanbhogue and Hannun, 2018). In order to convert SM lipids into phosphocholine and ceramide, SMases have to be active and functional to hydrolyze this process (Clarke et al, 2006;Bartke and Hannun, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…In order to convert SM lipids into phosphocholine and ceramide, SMases have to be active and functional to hydrolyze this process (Clarke et al, 2006;Bartke and Hannun, 2009). SM consisting of phosphocholine and ceramide or a phospho-ethanolamine head group is a type of sphingolipid found in all animal membranes (Hannun and Obeid, 2018;Shanbhogue and Hannun, 2018). It represents 85% of all sphingolipids in human and accounts to 10-20 mol % of the plasma membrane lipids (van Meer and Lisman, 2002;Futerman, 2006;Bartke and Hannun, 2009).…”

Section: Discussionmentioning

confidence: 99%

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Tick-Borne Flavivirus Inhibits Sphingomyelinase (IsSMase), a Venomous Spider Ortholog to Increase Sphingomyelin Lipid Levels for Its Survival in Ixodes scapularis Ticks

Regmi

Khanal

Neelakanta

et al. 2020

Front. Cell. Infect. Microbiol.

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Our previous study showed that cells from medically important arthropods, such as ticks, secrete extracellular vesicles (EVs) including exosomes that mediate transmission of flavivirus RNA and proteins to the human cells. Understanding the molecular determinants and mechanism(s) of arthropod-borne flavivirus transmission via exosome biogenesis is very important. In this current study, we showed that in the presence of tick-borne Langat Virus (LGTV; a member of tick-borne encephalitis virus complex), the expression of arthropod IsSMase, a sphingomyelinase D (SMase D) that catalyzes the hydrolytic cleavage of substrates like sphingomyelin (SM) lipids, was significantly reduced in both Ixodes scapularis ticks (in vivo) and in tick cells (in vitro). The IsSMase reduced levels correlated with down-regulation of its activity upon LGTV replication in tick cells. Our data show that LGTV-mediated suppression of IsSMase allowed accumulation of SM lipid levels that supported membrane-associated viral replication and exosome biogenesis. Inhibition of viral loads and SM lipid built up upon GW4869 inhibitor treatment reversed the IsSMase levels and restored its activity. Our results suggest an important role for this spider venomous ortholog IsSMase in regulating viral replication associated with membrane-bound SM lipids in ticks. In summary, our study not only suggests a novel role for arthropod IsSMase in tick-LGTV interactions but also provides new insights into its important function in vector defense mechanism(s) against tick-borne virus infection and in anti-viral pathway(s).

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Tick-Borne Flavivirus Inhibits Sphingomyelinase (IsSMase), a Venomous Spider Ortholog to Increase Sphingomyelin Lipid Levels for Its Survival in Ixodes scapularis Ticks

Regmi

Khanal

Neelakanta

et al. 2020

Front. Cell. Infect. Microbiol.

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“…It has been reported that free ARA is readily incorporated by S. mansoni (56), and likely activates the parasite voltage-gated channels, and enzymes, namely tegumentassociated nSMase with subsequent apical SM hydrolysis, and exposure of the otherwise hidden surface membrane antigens to antibody-mediated effector functions, and parasite demise. Sphingomyelin degradation leads to accumulation of intra worm apoptotic signals (57). Arachidonic acid, a powerful host phagocyte NADPH oxidase activator, contributes to inflammation via eliciting massive production of reactive oxygen (ROS) and nitrogen (RNS) species (58), which are harmful to the schistosomes and perhaps responsible for egg attrition, immediately upon trapping.…”

Section: Arachidonic Acid Is a Critical Mediator Of Protection In Thementioning

confidence: 99%

Arachidonic Acid Is a Safe and Efficacious Schistosomicide, and an Endoschistosomicide in Natural and Experimental Infections, and Cysteine Peptidase Vaccinated Hosts

2020

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Blood flukes of the genus Schistosoma are covered by a protective heptalaminated, double lipid bilayer surface membrane. Large amounts of sphingomyelin (SM) in the outer leaflet form with surrounding water molecules a tight hydrogen bond barrier, which allows entry of nutrients and prevents access of host immune effectors. Excessive hydrolysis of SM to phosphoryl choline and ceramide via activation of the parasite tegument-associated neutral sphingomyelinase (nSMase) with the polyunsaturated fatty acid, arachidonic acid (ARA) leads to parasite death, via allowing exposure of apical membrane antigens to antibody-dependent cell-mediated cytotoxicity (ADCC), and accumulation of the pro-apoptotic ceramide. Surface membrane nSMase represents, thus, a worm Achilles heel, and ARA a valid schistosomicide. Several experiments conducted in vitro using larval, juvenile, and adult Schistosoma mansoni and Schistosoma haematobium documented ARA schistosomicidal potential. Arachidonic acid schistosomicidal action was shown to be safe and efficacious in mice and hamsters infected with S. mansoni and S. haematobium , respectively, and in children with light S. mansoni infection. A combination of praziquantel and ARA led to outstanding cure rates in children with heavy S. mansoni infection. Additionally, ample evidence was obtained for the powerful ARA ovocidal potential in vivo and in vitro against S. mansoni and S. haematobium liver and intestine eggs. Studies documented ARA as an endogenous schistosomicide in the final mammalian and intermediate snail hosts, and in mice and hamsters, immunized with the cysteine peptidase-based vaccine. These findings together support our advocating the nutrient ARA as the safe and efficacious schistosomicide of the future.

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“…nSMases are further classified into anionic phospholipid (APL)independent nSMase1, APL-dependent nSMase2, a Bovine nSMase3, and a mitochondria-associated nSMase4. nSMase2 has been widely studied for its roles in cell growth, stress responses, and exosome release (11)(12)(13). Dysregulation in nSMase2 activity has been implicated in cancer, cardiovascular, and neurological conditions, such as Alzheimer's disease (14,15), thus making it an important therapeutic target.…”

mentioning

confidence: 99%

“…The NTD contains two hydrophobic segments, HS1 and HS2, that are important for APL-mediated allosteric activation of nSMase2. The first APL-binding site is between HS1 and HS2 on nSMase2, and the second APL-binding site includes a portion of the JX region (13,18). The insertion region is presumed to regulate nSMase2 through its five phosphorylation sites and calcineurin-binding site (19); however, deletion of this region does not affect basal nSMase2 activity (20).…”

mentioning

confidence: 99%

The juxtamembrane linker in neutral sphingomyelinase-2 functions as an intramolecular allosteric switch that activates the enzyme

Shanbhogue

Hoffmann

Airola

et al. 2019

Journal of Biological Chemistry

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Edited by George M. Carman Neutral sphingomyelinase 2 (nSMase2) produces the bioactive lipid ceramide and has important roles in neurodegeneration, cancer, and exosome formation. Although nSMase2 has low basal activity, it is fully activated by phosphatidylserine (PS). Previous work showed that interdomain interactions within nSMase2 are needed for PS activation. Here, we use multiple approaches, including small angle X-ray scattering, hydrogendeuterium exchange-MS, circular dichroism and thermal shift assays, and membrane yeast two-hybrid assays, to define the mechanism mediating this interdomain interactions within nSMase2. In contrast to what we previously assumed, we demonstrate that PS binding at the N-terminal and juxtamembrane regions of nSMase2 rather acts as a conformational switch leading to interdomain interactions that are critical to enzyme activation. Our work assigns a unique function for a class of linkers of lipid-activated, membrane-associated proteins. It indicates that the linker actively participates in the activation mechanism via intramolecular interactions, unlike the canonical linkers that typically aid protein dimerization or localization.

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Exploring the Therapeutic Landscape of Sphingomyelinases

Cited by 17 publications

References 140 publications

Tick-Borne Flavivirus Inhibits Sphingomyelinase (IsSMase), a Venomous Spider Ortholog to Increase Sphingomyelin Lipid Levels for Its Survival in Ixodes scapularis Ticks

Tick-Borne Flavivirus Inhibits Sphingomyelinase (IsSMase), a Venomous Spider Ortholog to Increase Sphingomyelin Lipid Levels for Its Survival in Ixodes scapularis Ticks

Arachidonic Acid Is a Safe and Efficacious Schistosomicide, and an Endoschistosomicide in Natural and Experimental Infections, and Cysteine Peptidase Vaccinated Hosts

The juxtamembrane linker in neutral sphingomyelinase-2 functions as an intramolecular allosteric switch that activates the enzyme

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