After viral fusion, capsids of the neurotropic herpes simplex virus are transported along microtubules (MT) to the nuclear pores for viral genome uncoating, nuclear transcription and replication. After assembly and egress from the nucleus, cytosolic capsids are transported to host membranes for secondary envelopment or to the axon terminal for further viral spread. Using GFP-tagged capsids, Cy3-labelled MT and cytosol, we have reconstituted viral capsid transport in vitro. In the presence of ATP, capsids moved along MT up to 30 mm. Blocking the function of dynactin, a cofactor of dynein and kinesin-2, inhibited the transport. Removing outer tegument proteins from the capsids increased in vitro motility. In contrast, capsids isolated from infected nuclei that were devoid of inner as well as outer tegument proteins showed little interaction with dynein and its cofactor dynactin. Our data suggest that the inner tegument of alphaherpesviruses contains viral receptors for MT motors. Herpes simplex virus type 1 (HSV1) is a neurotropic human alphaherpesvirus that initially infects the oral or perioral skin and mucosa before amplified virus enters local sensory and autonomic nerve endings (1). An HSV1 virion consists of a DNA-containing capsid that is covered by about 20 different capsid-associated and tegument proteins, and capsid and tegument are enveloped by a viral membrane (2). Most likely, capsids lose their envelope before moving to the neuronal cell bodies located in cranial ganglia (3-5). The viral dsDNA genome of 152 kb is injected into the nucleoplasm through the nuclear pore (6) and establishes a lifelong latent infection. Upon reactivation, progeny capsids, and possibly virions, contained in membrane vesicles are transported anterogradely to the peripheral nerve endings (7-12). In rare cases, reactivated virus is instead transported to the central nervous system causing life-threatening encephalitis (13).It has been predicted that it would take an HSV1 capsid with a diameter of 125 nm 231 years to diffuse 10 mm in the axonal cytoplasm (14). Instead of diffusion, viral particles use the host cytoskeleton for fast intracellular transport (1,15,16). Microtubules (MT) are long cytoskeletal filaments with biochemically distinct ends assembled from a/b-tubulin (17). The fast-growing plus-ends of MT usually point towards the plasma membrane and in neuronal axons towards the nerve terminals. The lessdynamic MT minus-ends are often stabilized by attachment to a MT-organizing centre located close to the nucleus. HSV1 loses its envelope during cell entry by fusion with the plasma membrane or with an endocytic membrane (18,19), and in epithelial as well as in neuronal cells, incoming capsids, possibly with associated tegument proteins, are transported along MT to the nucleus (20-23). Efficient virus assembly and egress also depend on MT (24,25), and progeny virus uses MT for efficient axonal transport to the synapse (11).Cytoplasmic dynein together with its cofactor dynactin powers most transport to MT minus-ends (26),...
Background: Hypusine modification of the eukaryotic initiation factor 5A (eIF-5A) represents a conserved post-translational modification that regulates translation. Results: Deletion of hypusine modification enzymes exerts strong phenotypes. eIF-5A2-deleted animals are viable and fertile. Conclusion: Both enzymatic steps of hypusine modification are essential for mammalian homeostasis, whereas the cancerrelated isoform eIF-5A2 is dispensable. Significance: eIF-5A2 might represent a safe therapeutic target.
Herpes simplex virus (HSV) immediate-early protein ICP0 is a transcriptional activator with E3 ubiquitin ligase activity that induces the degradation of ND10 proteins, including the promyelocytic leukemia protein (PML) and Sp100. Moreover, ICP0 has a role in the derepression of viral genomes and in the modulation of the host interferon response to virus infection. Here, we report that ICP0 interacts with SIAH-1, a cellular E3 ubiquitin ligase that is involved in multiple cellular pathways and is itself capable of mediating PML degradation. This novel virus-host interaction profoundly stabilized SIAH-1 and recruited this cellular E3 ligase into ICP0-containing nuclear bodies. Moreover, SIAH-1 mediated the polyubiquitination of HSV ICP0 in vitro and in vivo. After infection of SIAH-1 knockdown cells with HSV, higher levels of ICP0 were produced, ICP0 was less ubiquitinated, and the half-life of this multifunctional viral regulatory protein was increased. These results indicate an inhibitory role of SIAH-1 during lytic infection by targeting ICP0 for proteasomal degradation.ICP0 is a member of the class of immediate-early gene products of herpes simplex virus 1 and 2 (HSV-1 and -2), with homologs in other herpesvirus subfamilies. ICP0 is required for the efficient initiation of viral lytic infection and reactivation from latently infected neurons (reviewed in references 22, 34, 35, and 65). ICP0 appears to be a multifunctional regulator of gene expression that directly and indirectly interacts with numerous viral and cellular proteins. For example, these include the viral transcriptional activator ICP4, the cellular transcription factor BMAL1, the translation initiation factor 1␣, cell cycle regulators such as cyclins, and the tumor suppressor p53 (6,(45)(46)(47)81). ICP0 is also a component of viral particles, where it can be detected in a salt-resistant fraction of the tegument, suggesting it to be an inner tegument protein closely associated with the capsid (21,53,66).Early in infection, newly synthesized ICP0 localizes to discrete subnuclear structures, which are characterized by the presence of the promyelocytic leukemia protein (PML) and are variously referred to as nuclear domain 10 (ND10), Kremer bodies, PML nuclear bodies, or PML oncogenic domains (PODs). ND10 has been implicated in a variety of cellular processes, including the regulation of growth control, senescence, apoptosis, transformation, and antiviral responses (for reviews, see references 4, 15, and 24). During the early stage of infection, HSV genomes locate preferentially in the periphery of ND10, and these nuclear areas are considered to be the sites where viral transcription initiates (23, 55). Importantly, later in infection the ND10 components PML and Sp100, which is another major and constitutive component of ND10 (7,12,27), are rearranged and disrupted by the E3 ubiquitin ligase activity of ICP0, which is mediated by a zinc-binding RING finger domain near its amino terminus (8,28,56,57). Nevertheless, ubiquitination of PML by ICP0 was not...
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