Lipase Activities of p37, the Major Envelope Protein of Vaccinia Virus

Baek, Seung‐Hun; Kwak, Jong‐Young; Lee, S. H.; Lee, T.; Ryu, Sung Ho; Uhlinger, David J.; Lambeth, J. David

doi:10.1074/jbc.272.51.32042

Cited by 50 publications

(41 citation statements)

References 34 publications

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“…Loss of the A56 or A33 protein did not affect this phenomenon. The F13 protein has sequence similarity to mammalian phospholipase (PL) D and has PL activity to metabolize phospholipids to phosphatidic acids (36)(37)(38) and so was an attractive candidate for involvement in membrane dissolution. However, F13 is important during morphogenesis for intracellular enveloped virus formation, and so its role in entry is difficult to study because without it very little EEV is produced (35).…”

Section: Resultsmentioning

confidence: 99%

Ligand-induced and nonfusogenic dissolution of a viral membrane

Law

Carter²,

Roberts³

et al. 2006

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

115

118

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Hitherto, all enveloped viruses were thought to shed their lipid membrane during entry into cells by membrane fusion. The extracellular form of Vaccinia virus has two lipid envelopes surrounding the virus core, and consequently a single fusion event will not deliver a naked core into the cell. Here we report a previously underscribed mechanism in which the outer viral membrane is disrupted by a ligand-induced nonfusogenic reaction, followed by the fusion of the inner viral membrane with the plasma membrane and penetration of the virus core into the cytoplasm. The dissolution of the outer envelope depends on interactions with cellular polyanionic molecules and requires the virus glycoproteins A34 and B5. This discovery represents a remarkable example of how viruses manipulate biological membranes, solves the topological problem of how a double-enveloped virus enters cells, reveals a new effect of polyanions on viruses, and provides a therapeutic approach for treatment of poxvirus infections, such as smallpox.antiviral therapy ͉ extracellular enveloped virus ͉ membrane dissolution ͉ Vaccinia virus ͉ virus entry H itherto, membrane fusion was the only known mechanism by which enveloped viruses overcome the lipid barrier to enter and replicate in cells (1, 2). Here we show that the extracellular enveloped virus (EEV) of Vaccinia virus (VACV) sheds its outer lipid membrane by a ligand-dependent nonfusogenic mechanism.VACV replication produces several distinct virions: the intracellular mature virus (IMV), intracellular enveloped virus, cellassociated enveloped virus (CEV), and EEV (3, 4). IMV is surrounded by one lipid membrane (5-9) and is physically robust to aid virus transmission between hosts. CEV and EEV are IMV particles wrapped with an additional membrane derived from the trans-Golgi network (10) or endosomes (11) and are responsible for virus dissemination within the host (4). This extra lipid envelope (EEV membrane) and the associated virus and host membrane proteins serve to protect the IMV particle within from immune surveillance and may contribute to a broader cell tropism of the virus (4). Recently, we provided unequivocal electron micrographs showing that IMV enters by fusion with the plasma membrane (8), consistent with previous reports (6,12,13), and the recent genetic evidence for entry by fusion (14-17). Once the naked core has entered the cytoplasm, it moves deeper into the cell on microtubules (18). However, for VACV EEV, the additional EEV membrane presents an unexplained topological problem for entry, because fusion of the EEV outer envelope with the plasma membrane or the membrane of an intracellular vesicle will release only an IMV, instead of a naked core, into the cytosol. For a recent review of VACV entry, see ref.19.Here we studied the entry of EEV by immuno-EM and demonstrated that the EEV outer membrane is disrupted at the point of cell contact after binding. This enables the IMV within to enter the cell by fusion with the plasma membrane. The ligands required for membrane rupture were ...

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Section: Resultsmentioning

confidence: 99%

Ligand-induced and nonfusogenic dissolution of a viral membrane

Law

Carter²,

Roberts³

et al. 2006

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

115

118

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“…Unsaturated fatty acids block HIV budding [126] Mycobactin mediates iron supply within macrophages [32] FA Affinity of HIV Gag protein is regulated by myristoyl switch [127] Presentation of glycerophospholipids, sulfolipids and mycolates via CD1 receptors [58,132,133] GP Golgi-derived viruses have different phospholipid (incl semilysobisphosphatidic acid) composition depending on the precise site of budding [7,128] HIV-like particle assembly is regulated by inositol phosphates [129] HIV-1 Gag targeting is regulated by PIP2 [130] Vaccinia virus envelope protein p37 has lipase activity [131] Nef transports cholesterol to site of HIV budding [134] ST Budding occurs from glycolipid-enriched membrane lipid rafts [8,[135][136][137] Table summarizing the reported involvement of lipids, both from the host as well as the pathogen, during various stages of host-pathogen interaction ( Fig. 1).…”

Section: Glmentioning

confidence: 99%

Lipidomics of host–pathogen interactions

Wenk

2006

FEBS Letters

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The cell biology of intracellular pathogens (viruses, bacteria, eukaryotic parasites) has provided us with molecular information of host-pathogen interactions. As a result it is becoming increasingly evident that lipids play important roles at various stages of host-pathogen interactions. They act in first line recognition and host cell signaling during pathogen docking, invasion and intracellular trafficking. Lipid metabolism is a housekeeping function in energy homeostasis and biomembrane synthesis during pathogen replication and persistence. Lipids of enormous chemical diversity play roles as immunomodulatory factors. Thus, novel biochemical analytics in combination with cell and molecular biology are a promising recipe for dissecting the roles of lipids in host-pathogen interactions.

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“…Some viruses have been shown to code for their own lipolytic enzymes. For example, the major envelope protein of vaccinia virus, p37, exhibits multiple lipolytic activities (5,7). It has been recently reported that a parvovirus contains a soluble PLA2 (sPLA2)-type activity encoded by the virus itself (14,35).…”

Section: Human Cytomegalovirus (Hcmv) Is a ␤ Herpesvirus That Causes mentioning

confidence: 99%

Human Cytomegalovirus Carries a Cell-Derived Phospholipase A2 Required for Infectivity

Allal

Buisson-Brenac

Marion

et al. 2004

J Virol

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Human cytomegalovirus (HCMV) is known to carry host cell-derived proteins and mRNAs whose role in cell infection is not understood. We have identified a phospholipase A2 (PLA2) activity borne by HCMV by using an assay based on the hydrolysis of fluorescent phosphatidylcholine. This activity was found in all virus strains analyzed and in purified strains. It was calcium dependent and was sensitive to inhibitors of cytosolic PLA2 (cPLA2) but not to inhibitors of soluble PLA2 or calcium-independent PLA2. No other phospholipase activity was detected in the virus. Purified virus was found to contain human cellular cPLA2␣, as detected by monoclonal antibody. No homology with PLA2 was found in the genome of HCMV, indicating that HCMV does not code for a PLA2. Decreased de novo expression of immediate-early proteins 1 and 2 (IE1 and IE2), tegument phosphoprotein pp65, and virus production was observed when HCMV was treated with inhibitors of cPLA2. Cell entry of HCMV was not altered by those inhibitors, suggesting the action of cPLA2 was postentry. Together, our results indicate a selective sorting of a cell-derived cPLA2 during HCMV maturation, which is further required for infectivity.

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Lipase Activities of p37, the Major Envelope Protein of Vaccinia Virus

Cited by 50 publications

References 34 publications

Ligand-induced and nonfusogenic dissolution of a viral membrane

Ligand-induced and nonfusogenic dissolution of a viral membrane

Lipidomics of host–pathogen interactions

Human Cytomegalovirus Carries a Cell-Derived Phospholipase A2 Required for Infectivity

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