Functions of phospholipid flippases

Tanaka, Kazuma; Fujimura-Kamada, Konomi; Yamamoto, Takaharu

doi:10.1093/jb/mvq140

Cited by 80 publications

(79 citation statements)

References 88 publications

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“…Consistent with the concept of apoptotic mimicry, the presence of PS in viral membranes has been reported for several viruses, including Pichinde virus, vesicular stomatitis virus (VSV), vaccinia virus, and DENV (9,11,12). Although phosphatidylethanolamine (PE) and PS are restricted to the inner leaflet in eukaryotic membranes, they are believed to redistribute to both leaflets of the viral membrane as a result of the absence of flippases to maintain membrane asymmetry (13,14).T-cell Ig mucin domain (TIM) proteins are PS receptors, with three members in humans: TIM1, TIM3, and TIM4. These proteins are type I cell-surface GPs consisting of four major domains: an Ig variable (IgV)-like N-terminal domain containing a high-affinity binding site for PS, a heavily O-glycosylated mucin-like domain, a transmembrane domain, and a cytoplasmic domain.…”

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Virion-associated phosphatidylethanolamine promotes TIM1-mediated infection by Ebola, dengue, and West Nile viruses

Richard

Zhang

Park

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

112

105

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Phosphatidylserine (PS) receptors contribute to two crucial biological processes: apoptotic clearance and entry of many enveloped viruses. In both cases, they recognize PS exposed on the plasma membrane. Here we demonstrate that phosphatidylethanolamine (PE) is also a ligand for PS receptors and that this phospholipid mediates phagocytosis and viral entry. We show that a subset of PS receptors, including T-cell immunoglobulin (Ig) mucin domain protein 1 (TIM1), efficiently bind PE. We further show that PE is present in the virions of flaviviruses and filoviruses, and that the PE-specific cyclic peptide lantibiotic agent Duramycin efficiently inhibits the entry of West Nile, dengue, and Ebola viruses. The inhibitory effect of Duramycin is specific: it inhibits TIM1-mediated, but not L-SIGNmediated, virus infection, and it does so by blocking virus attachment to TIM1. We further demonstrate that PE is exposed on the surface of apoptotic cells, and promotes their phagocytic uptake by TIM1-expressing cells. Together, our data show that PE plays a key role in TIM1-mediated virus entry, suggest that disrupting PE association with PS receptors is a promising broad-spectrum antiviral strategy, and deepen our understanding of the process by which apoptotic cells are cleared. M embers of the filovirus and flavivirus families are the causative agents of life-threatening diseases. Ebola virus (EBOV), a filovirus, causes hemorrhagic fever with an average case fatality rate as high as 65% (1). Although there are EBOV vaccine candidates (2, 3), there is currently no licensed vaccine or treatment. Dengue virus (DENV) and West Nile virus (WNV) belong to the flavivirus family. Both are transmitted to humans through mosquito bites and can cause lethal hemorrhagic fever (in the case of DENV) or severe neurological diseases (in the case of WNV) (4, 5). Flaviviruses are emerging as major health concerns in tropical and subtropical areas worldwide. More than one third of the world's population is estimated to be at risk for DENV infection, with approximately 400 million people infected yearly (6). There are currently no approved vaccines or therapeutic agents against DENV or WNV.Virus entry into host cells typically initiates with the interaction between viral entry glycoproteins (GPs) and a receptor or coreceptor expressed at the surface of the target cell. Viruses also use less specific mechanisms to localize to target cell membranes, for example through GP association with various attachment factors (7). During the past few years, it has been increasingly recognized that many viruses also use a strategy known as apoptotic mimicry to promote their association with, and internalization into their target cells (8). Receptors for phospholipids, specifically phosphatidylserine (PS), normally involved in the clearance of apoptotic cells, markedly enhance the infection of a number of enveloped viruses. These PS receptors are presumed to engage PS on the virion membrane rather than the viral entry protein (9, 10). Enveloped viruses acquire...

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confidence: 65%

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confidence: 66%

Virion-associated phosphatidylethanolamine promotes TIM1-mediated infection by Ebola, dengue, and West Nile viruses

Richard

Zhang

Park

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

112

105

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“…Second, Ypk1 is a pivotal component of regulatory circuitry that imposes a balance between the pool of complex sphingolipids and the amount of aminophospholipids in the outer leaflet (12). Specifically, among transposon insertions that improve the temperature-sensitive growth of ypk1 ts ypk2Δ cells (14), we found loss-of-function mutations in DNF3, one of five genes encoding inward-directed P-type ATPases (flippases) that transport aminophospholipids (18,19), suggesting that one role of Ypk1 is to inhibit lipid flippase action, directly or indirectly. Indeed, Ypk1 does not act on the flippases directly, but does so indirectly by phosphorylating and thereby inhibiting the flippase protein kinase 1 (Fpk1; and its paralog Fpk2), which are known flippase activators (20) that require a complex sphingolipid, mannosylinositol phosphorylceramide (MIPC), for their optimal function (12).…”

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confidence: 99%

Protein kinase Ypk1 phosphorylates regulatory proteins Orm1 and Orm2 to control sphingolipid homeostasis in Saccharomyces cerevisiae

Roelants

Breslow

Muir

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

261

426

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The Orm family proteins are conserved integral membrane proteins of the endoplasmic reticulum that are key homeostatic regulators of sphingolipid biosynthesis. Orm proteins bind to and inhibit serine: palmitoyl-coenzyme A transferase, the first enzyme in sphingolipid biosynthesis. In Saccharomyces cerevisiae, Orm1 and Orm2 are inactivated by phosphorylation in response to compromised sphingolipid synthesis (e.g., upon addition of inhibitor myriocin), thereby restoring sphingolipid production. We show here that protein kinase Ypk1, one of an essential pair of protein kinases, is responsible for this regulatory modification. Myriocin-induced hyperphosphorylation of Orm1 and Orm2 does not occur in ypk1Δ cells, and immunopurified Ypk1 phosphorylates Orm1 and Orm2 robustly in vitro exclusively on three residues that are known myriocin-induced sites. Furthermore, the temperature-sensitive growth of ypk1 ts ypk2Δ cells is substantially ameliorated by deletion of ORM genes, confirming that a primary physiological role of Ypk1-mediated phosphorylation is to negatively regulate Orm function. Ypk1 immunoprecipitated from myriocin-treated cells displays a higher specific activity for Orm phosphorylation than Ypk1 from untreated cells. To identify the mechanism underlying Ypk1 activation, we systematically tested several candidate factors and found that the target of rapamycin complex 2 (TORC2) kinase plays a key role. In agreement with prior evidence that a TORC2-dependent site in Ypk1(T662) is necessary for cells to exhibit a wild-type level of myriocin resistance, a Ypk1 (T662A) mutant displays only weak Orm phosphorylation in vivo and only weak activation in vitro in response to sphingolipid depletion. Additionally, sphingolipid depletion increases phosphorylation of Ypk1 at T662. Thus, Ypk1 is both a sensor and effector of sphingolipid level, and reduction in sphingolipids stimulates Ypk1, at least in part, via TORC2-dependent phosphorylation.cell regulation | plasma membrane

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“…In this phospholipid asymmetry, phosphatidylcholine (PC) 2 is predominantly distributed in the outer leaflet facing extracellular space (exoplasmic leaflet), whereas phosphatidylethanolamine (PE) and phosphatidylserine (PS) are distributed in the inner leaflet facing the cytoplasm (cytoplasmic leaflet). The type 4 subfamily of P-type ATPase (P4-ATPase) seems to play an essential role to generate, maintain, and regulate phospholipid asymmetry by working as a "flippase," which translocates aminophospholipids from the exoplasmic leaflet to the cytoplasmic one in an energy-dependent manner (1)(2)(3)(4)(5).…”

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Phospholipid Flippases Lem3p-Dnf1p and Lem3p-Dnf2p Are Involved in the Sorting of the Tryptophan Permease Tat2p in Yeast

Hachiro

Yamamoto

Nakano

et al. 2013

Journal of Biological Chemistry

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Background: Lem3p-Dnf1p and Lem3p-Dnf2p are phospholipid flippases that generate phospholipid asymmetry in yeast. Results:The tryptophan permease Tat2p is missorted from the trans-Golgi network to the vacuole in the lem3⌬ mutant. Conclusion: Phospholipid asymmetry supports plasma membrane transport of Tat2p by inhibiting its improper ubiquitination at the trans-Golgi network. Significance: Phospholipid asymmetry may be involved in proper sorting of membrane proteins.

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Functions of phospholipid flippases

Cited by 80 publications

References 88 publications

Virion-associated phosphatidylethanolamine promotes TIM1-mediated infection by Ebola, dengue, and West Nile viruses

Virion-associated phosphatidylethanolamine promotes TIM1-mediated infection by Ebola, dengue, and West Nile viruses

Protein kinase Ypk1 phosphorylates regulatory proteins Orm1 and Orm2 to control sphingolipid homeostasis in Saccharomyces cerevisiae

Phospholipid Flippases Lem3p-Dnf1p and Lem3p-Dnf2p Are Involved in the Sorting of the Tryptophan Permease Tat2p in Yeast

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