Lipids and Proteins Act in Opposing Manners To Regulate Polyomavirus Infection

Qian, Mengding; Tsai, Billy

doi:10.1128/jvi.01093-10

Cited by 28 publications

(27 citation statements)

References 37 publications

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“…The virus infectious pathway to ER is directed from the plasma membrane by the ganglioside receptor [9], [17] and requires acidic environment of the endosomes [3], [9]. Previous reports pointed to the importance of virus transfer via early and late endosomal compartments as overexpression of dominant-negative mutant of Rab5 [3], [9] or Rab7 GTPase [9] inhibited MPyV infection.…”

Section: Introductionmentioning

confidence: 99%

Involvement of Microtubular Network and Its Motors in Productive Endocytic Trafficking of Mouse Polyomavirus

et al. 2014

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Infection of non-enveloped polyomaviruses depends on an intact microtubular network. Here we focus on mouse polyomavirus (MPyV). We show that the dynamics of MPyV cytoplasmic transport reflects the characteristics of microtubular motor-driven transport with bi-directional saltatory movements. In cells treated with microtubule-disrupting agents, localization of MPyV was significantly perturbed, the virus was retained at the cell periphery, mostly within membrane structures resembling multicaveolar complexes, and at later times post-infection, only a fraction of the virus was found in Rab7-positive endosomes and multivesicular bodies. Inhibition of cytoplasmic dynein-based motility by overexpression of dynamitin affected perinuclear translocation of the virus, delivery of virions to the ER and substantially reduced the numbers of infected cells, while overexpression of dominant-negative form of kinesin-1 or kinesin-2 had no significant impact on virus localization and infectivity. We also found that transport along microtubules was important for MPyV-containing endosome sequential acquisition of Rab5, Rab7 and Rab11 GTPases. However, in contrast to dominant-negative mutant of Rab7 (T22N), overexpression of dominant-negative mutant Rab11 (S25N) did not affect the virus infectivity. Altogether, our study revealed that MPyV cytoplasmic trafficking leading to productive infection bypasses recycling endosomes, does not require the function of kinesin-1 and kinesin-2, but depends on functional dynein-mediated transport along microtubules for translocation of the virions from peripheral, often caveolin-positive compartments to late endosomes and ER – a prerequisite for efficient delivery of the viral genome to the nucleus.

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Section: Introductionmentioning

confidence: 99%

Involvement of Microtubular Network and Its Motors in Productive Endocytic Trafficking of Mouse Polyomavirus

et al. 2014

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“…Subsequently, the mPyV was shown to bind to sialic acids present on the ganglioside receptors GD1a and GT1b (461,499). Although mPyV utilizes gangliosides for productive infection, the virus will bind to sialic acids present on glycoproteins (397). Binding of mPyV to cell surface glycoproteins targeted the virus to a nonproductive pathway for degradation, suggesting that these glycoproteins represent nonproductive pseudoreceptors.…”

Section: Virus Receptorsmentioning

confidence: 99%

Molecular Biology, Epidemiology, and Pathogenesis of Progressive Multifocal Leukoencephalopathy, the JC Virus-Induced Demyelinating Disease of the Human Brain

et al. 2012

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SUMMARY Progressive multifocal leukoencephalopathy (PML) is a debilitating and frequently fatal central nervous system (CNS) demyelinating disease caused by JC virus (JCV), for which there is currently no effective treatment. Lytic infection of oligodendrocytes in the brain leads to their eventual destruction and progressive demyelination, resulting in multiple foci of lesions in the white matter of the brain. Before the mid-1980s, PML was a relatively rare disease, reported to occur primarily in those with underlying neoplastic conditions affecting immune function and, more rarely, in allograft recipients receiving immunosuppressive drugs. However, with the onset of the AIDS pandemic, the incidence of PML has increased dramatically. Approximately 3 to 5% of HIV-infected individuals will develop PML, which is classified as an AIDS-defining illness. In addition, the recent advent of humanized monoclonal antibody therapy for the treatment of autoimmune inflammatory diseases such as multiple sclerosis (MS) and Crohn's disease has also led to an increased risk of PML as a side effect of immunotherapy. Thus, the study of JCV and the elucidation of the underlying causes of PML are important and active areas of research that may lead to new insights into immune function and host antiviral defense, as well as to potential new therapies.

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“…However, JCPyV does not colocalize with Rab7-GFP during entry and a Rab7-DN mutant does not inhibit infection, indicating that JCPyV does not enter maturing endosomes, late endosomes, or endolysosomes (Querbes et al, 2006; Qian et al, 2009; Qian et al, 2010; Engel et al, 2011). In addition, expression of a Rab11-DN mutant has no effect on JCPyV infectivity, suggesting that recycling endosomes do not play a role in infection.…”

Section: Intracellular Transport Of Jcpyvmentioning

confidence: 99%

“…Intracellular transport of JCPyV appears to differ from that of other polyomaviruses. SV40 and mPyV, which bind to the gangliosides GM1 and GD1a, respectively, undergo endocytosis by caveolar-or lipid-dependent mechanisms to enter early endosomes following receptor engagement (Pelkmans et al, 2001; Campanero-Rhodes et al, 2007; Qian et al, 2009; Ewers et al, 2010; Qian et al, 2010). SV40 is then transported to Cav-1-and Rab7-positive late endosomes, while mPyV is transported to Rab7-positive endosomes.…”

Section: Intracellular Transport Of Jcpyvmentioning

confidence: 99%

JC polyomavirus attachment, entry, and trafficking: unlocking the keys to a fatal infection

2014

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The human JC polyomavirus (JCPyV) causes a lifelong persistent infection in the reno-urinary tract in the majority of the adult population worldwide. In healthy individuals infection is asymptomatic, while in immunocompromised individuals the virus can spread to the central nervous system and cause a fatal demyelinating disease known as progressive multifocal leukoencephalopathy (PML). There are currently very few treatment options for this rapidly progressing and devastating disease. Understanding the basic biology of JCPyV-host cell interactions is critical for the development of therapeutic strategies to prevent or treat PML. Research in our laboratory has focused on gaining a detailed mechanistic understanding of the initial steps in the JCPyV life cycle in order to define how JCPyV selectively targets cells in the kidney and brain. JCPyV requires sialic acids to attach to host cells and initiate infection, and JCPyV demonstrates specificity for the oligosaccharide lactoseries tetrasaccharide c (LSTc) with an α2,6-linked sialic acid. Following viral attachment, JCPyV entry is facilitated by the 5-hydroxytryptamine (5-HT)2 family of serotonin receptors via clathrin-dependent endocytosis. JCPyV then undergoes retrograde transport to the endoplasmic reticulum (ER) where viral disassembly begins. A novel retrograde transport inhibitor termed Retro-2cycl prevents trafficking of JCPyV to the ER and inhibits both initial virus infection and infectious spread in cell culture. Understanding the molecular mechanisms by which JCPyV establishes infection will open up new avenues for the prevention or treatment of virus-induced disease.

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Lipids and Proteins Act in Opposing Manners To Regulate Polyomavirus Infection

Cited by 28 publications

References 37 publications

Involvement of Microtubular Network and Its Motors in Productive Endocytic Trafficking of Mouse Polyomavirus

Involvement of Microtubular Network and Its Motors in Productive Endocytic Trafficking of Mouse Polyomavirus

Molecular Biology, Epidemiology, and Pathogenesis of Progressive Multifocal Leukoencephalopathy, the JC Virus-Induced Demyelinating Disease of the Human Brain

JC polyomavirus attachment, entry, and trafficking: unlocking the keys to a fatal infection

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