Alphaherpesvirus Infection Disrupts Mitochondrial Transport in Neurons

Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
Cell host & microbe (Impact Factor: 12.33). 05/2012; 11(5):504-14. DOI: 10.1016/j.chom.2012.03.005
Source: PubMed


Mitochondria are dynamic organelles that are essential for cellular metabolism but can be functionally disrupted during pathogen infection. In neurons, mitochondria are transported on microtubules via the molecular motors kinesin-1 and dynein and recruited to energy-requiring regions such as synapses. Previous studies showed that proteins from pseudorabies virus (PRV), an alphaherpesvirus, localize to mitochondria and affect mitochondrial function. We show that PRV and herpes simplex virus type 1 (HSV-1) infection of rodent superior cervical ganglion (SCG) neurons disrupts mitochondrial motility and morphology. During PRV infection, glycoprotein B (gB)-dependent fusion events result in electrical coupling of neurons and increased action potential firing rates. Consequently, intracellular [Ca(2+)] increases and alters mitochondrial dynamics through a mechanism involving the Ca(2+)-sensitive cellular protein Miro and reduced recruitment of kinesin-1 to mitochondria. This disruption in mitochondrial dynamics is required for efficient growth and spread of PRV, indicating that altered mitochondrial transport enhances alphaherpesvirus pathogenesis and infection.

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    • "(C) Quantification of virus infectivity shown in B. Mean GFP fluorescence Vesicular organelles positive for GFP-Rab7 and GFP-NPC1, a lyso/LE component implicated in cell entry by Ebola virus (Carette et al., 2011; Côté et al., 2011), also spread more broadly throughout the cytoplasm in response to Ad5 infection, similar to LysoTracker-positive vesicles (Fig. 4 C and Table 1). In contrast, markers for Golgi elements (N-acetylglucosaminyltransferase I [NAGT]–GFP) and mitochondria (MitoTracker), which change their motility and morphology during herpes virus infection (Kramer and Enquist, 2012), showed no obvious evidence of redistribution (Fig. 4 C and Table 1). These data are consistent with LysoTracker localization to organelles positive for GFP-Lamp1, -NPC1, -Rab7, and -RILP but not for GFP-Rab5 or -NAGT (Fig. S5) and indicate a specific dispersal of lyso/LE during Ad5 infection. "
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    ABSTRACT: Cytoplasmic dynein is responsible for transport of several viruses to the nucleus. Adenovirus recruits dynein directly. Transport depends on virus-induced activation of protein kinase A (PKA) and other cellular protein kinases, whose roles in infection are poorly understood. We find that PKA phosphorylates cytoplasmic dynein at a novel site in light intermediate chain 1 (LIC1) that is essential for dynein binding to the hexon capsid subunit and for virus motility. Surprisingly, the same LIC1 modification induces a slow, but specific, dispersal of lysosomes (lyso)/late endosomes (LEs) that is mediated by inhibition of a newly identified LIC1 interaction with the RILP (Rab7-interacting lysosomal protein). These results identify an organelle-specific dynein regulatory modification that adenovirus uses for its own transport. PKA-mediated LIC1 phosphorylation causes only partial lyso/LE dispersal, suggesting a role for additional, parallel mechanisms for dynein recruitment to lyso/LEs. This arrangement provides a novel means to fine tune transport of these organelles in response to infection as well as to developmental and physiological cues.
    The Journal of Cell Biology 04/2014; 205(2):163-77. DOI:10.1083/jcb.201307116 · 9.83 Impact Factor
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    • "We hypothesize that incorporation of Us9 and these SNARE proteins within the same membrane microdomains is functionally required for efficient spread of infection. Furthermore, we recently demonstrated that alphaherpesvirus infection disrupts mitochondrial motility in axons (Kramer and Enquist, 2012). Additional work is needed to determine whether the dynamics of synaptic vesicles and other cellular axonal cargoes may be altered. "
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    ABSTRACT: During infection of the nervous system, alphaherpesviruses-including pseudorabies virus (PRV)-use retrograde axonal transport to travel toward the neuronal cell body and anterograde transport to traffic back to the cell periphery upon reactivation from latency. The PRV protein Us9 plays an essential but unknown role in anterograde viral spread. To determine Us9 function, we identified viral and host proteins that interact with Us9 and explored the role of KIF1A, a microtubule-dependent kinesin-3 motor involved in axonal sorting and transport. Viral particles are cotransported with KIF1A in axons of primary rat superior cervical ganglion neurons, and overexpression or disruption of KIF1A function, respectively, increases and reduces anterograde capsid transport. Us9 and KIF1A interact early during infection with the aid of additional viral protein(s) but exhibit diminished binding at later stages, when capsids typically stall in axons. Thus, alphaherpesviruses repurpose the axonal transport and sorting pathway to spread within their hosts.
    Cell host & microbe 12/2012; 12(6):806-14. DOI:10.1016/j.chom.2012.10.013 · 12.33 Impact Factor
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    ABSTRACT: Mitochondria are dynamic organelles with many functions. In this issue of Cell Host & Microbe, Kramer and Enquist (2012) show that mitochondrial motility and morphology are disrupted during alphaherpesvirus infection, which aids viral replication and transport in neurons.
    Cell host & microbe 05/2012; 11(5):420-1. DOI:10.1016/j.chom.2012.05.001 · 12.33 Impact Factor
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