Role of Rab GTPases in HSV-1 infection: Molecular understanding of viral maturation and egress

Raza, Sohail; Alvisi, Gualtiero; Shahin, Farzana; Husain, Urooj; Rabbani, Masood; Yaqub, Tahir; Anjum, Aftab Ahmad; Sheikh, Ali Ahmad; Nawaz, Muhammad; Ali, Muhammad Asad

doi:10.1016/j.micpath.2018.03.028

Cited by 18 publications

(17 citation statements)

References 110 publications

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“…CK2 has been reported to be able to directly phosphorylate viral proteins, especially tegument proteins, which are associated with the early phase of the HSV‐1 virion life cycle . The Rab family of GTPases is another example that is known to be important for the assembly and egress of viruses, including PRV and HSV‐1 . We identified multiple Rab proteins, including Rab1a, Rab1b, Rab2a, Rab5c, Rab6a, Rab7, Rab11b, Rab14, and Rab34, although their functional implications need further study.…”

Section: Discussionmentioning

confidence: 93%

Proteomics Analysis Identifies IRSp53 and Fascin as Critical for PRV Egress and Direct Cell–Cell Transmission

Miao

Xia

et al. 2019

Proteomics

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Pseudorabies virus (PRV) has been widely used as a live trans‐synaptic tracer for mapping neuronal circuits. Systematically identifying mature PRV virion proteomes and defining co‐purified host proteins are necessary to fully understand the detailed mechanism underlying PRV transmission processes. Here, a PRV virion purification strategy based on sorting with flow cytometry is developed and the mature extracellular and intracellular PRV virion proteomes using LC coupled with MS/MS are characterized. In addition to viral proteins, a large number of host proteins are also identified, including proteins related to actin cytoskeletal dynamics and membrane protrusion. How many of these host proteins are true virion components are unknown and the majority of these may not be. Through functional analysis, it is found that IRSp53 and fascin are critical for the egress process and play a role in direct cell–cell transmission. Moreover, it is shown that CDC42 and Rac1 are also involved in the production of mature extracellular virions. The results suggest that the formation of the filopodia‐like cytoskeleton and the rearrangement of the membrane, which are both associated with IRSp53 and fascin, may be important for the transmission of viruses used in neuronal tracing.

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Section: Discussionmentioning

confidence: 93%

Proteomics Analysis Identifies IRSp53 and Fascin as Critical for PRV Egress and Direct Cell–Cell Transmission

Miao

Xia

et al. 2019

Proteomics

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“…If, as we suggest here, HSV re-activation is a risk factor for brain pathology such as (but not limited to) AD, then could inhibition of a specific Rab GTPase be a potential therapy? This idea has been proposed previously (Stein et al, 2003; Raza et al, 2018). HSV is not the only pathogen to recruit Rabs.…”

Section: Rabs As Targets For Drug Therapy Of Herpes-associated Cognitmentioning

confidence: 96%

“…Other knock-down experiments demonstrated a role for Rab5 and 11 in viral entry into epithelial cells through the endocytic pathway (Hollinshead et al, 2012; Raza et al, 2018; Spearman, 2018). This study also suggested that these Rabs are involved in recycling viral glycoproteins from the plasma membrane to the trans -Golgi network where they may be recruited for secondary envelopment.…”

Section: Rab Proteins In Hsv Life Cyclementioning

confidence: 99%

“…Rabs have also been implicated in cancer progression, with the consequence that targeted Rab inhibitors are under development (Salehi et al, 2009; Hong et al, 2010; Agola et al, 2015; Raza et al, 2018). The ubiquitous activity of Rabs in all aspect of intracellular membrane dynamics requires that any such pharmaceutical intervention be tightly directed to the pathologic process.…”

Section: Rabs As Targets For Drug Therapy Of Herpes-associated Cognitmentioning

confidence: 99%

“…Thus, most steps in its life cycle depend on membrane trafficking within infected cells. Hence the Rab proteins, small GTPases, which are master regulators of cellular membrane dynamics (Schwartz et al, 2007; Zhen and Stenmark, 2015; Pfeffer, 2017), are thought to play intimate roles in many stages of HSV infection, transport, envelopment and egress (Raza et al, 2018; Spearman, 2018). Emerging exciting evidence links HSV re-activation in the brain with Alzheimer’s disease (AD; Itzhaki et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Herpes Simplex Virus, Alzheimer’s Disease and a Possible Role for Rab GTPases

Bearer

2019

Front. Cell Dev. Biol.

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Herpes simplex virus (HSV) is a common pathogen, infecting 85% of adults in the United States. After reaching the nucleus of the long-lived neuron, HSV may enter latency to persist throughout the life span. Re-activation of latent herpesviruses is associated with progressive cognitive impairment and Alzheimer’s disease (AD). As an enveloped DNA virus, HSV exploits cellular membrane systems for its life cycle, and thereby comes in contact with the Rab family of GTPases, master regulators of intracellular membrane dynamics. Knock-down and overexpression of specific Rabs reduce HSV production. Disheveled membrane compartments could lead to AD because membrane sorting and trafficking are crucial for synaptic vesicle formation, neuronal survival signaling and Abeta production. Amyloid precursor protein (APP), a transmembrane glycoprotein, is the parent of Abeta, the major component of senile plaques in AD. Up-regulation of APP expression due to HSV is significant since excess APP interferes with Rab5 endocytic trafficking in neurons. Here, we show that purified PC12-cell endosomes transport both anterograde and retrograde when injected into the squid giant axon at rates similar to isolated HSV. Intracellular HSV co-fractionates with these endosomes, contains APP, Rab5 and TrkA, and displays a second membrane. HSV infected PC12 cells up-regulate APP expression. Whether interference with Rabs has a specific effect on HSV or indirectly affects membrane compartment dynamics co-opted by virus needs further study. Ultimately Rabs, their effectors or their membrane-binding partners may serve as handles to reduce the impact of viral re-activation on cognitive function, or even as more general-purpose anti-microbial therapies.

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