Virus-Induced Chaperone-Enriched (VICE) Domains Function as Nuclear Protein Quality Control Centers during HSV-1 Infection

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Abstract
Virus-Induced Chaperone-Enriched (VICE) domains form adjacent to nuclear viral replication compartments (RC) during the early stages of HSV-1 infection. Between 2 and 3 hours post infection at a MOI of 10, host protein quality control machinery such as molecular chaperones (e.g. Hsc70), the 20S proteasome and ubiquitin are reorganized from a diffuse nuclear distribution pattern to sequestration in VICE domains. The observation that VICE domains contain putative misfolded proteins suggests that they may be similar to nuclear inclusion bodies that form under conditions in which the protein quality control machinery is overwhelmed by the presence of misfolded proteins. The detection of Hsc70 in VICE domains, but not in nuclear inclusion bodies, indicates that Hsc70 is specifically reorganized by HSV-1 infection. We hypothesize that HSV-1 infection induces the formation of nuclear protein quality control centers to remodel or degrade aberrant nuclear proteins that would otherwise interfere with productive infection. Detection of proteolytic activity in VICE domains suggests that substrates may be degraded by the 20S proteasome in VICE domains. FRAP analysis reveals that GFP-Hsc70 is dynamically associated with VICE domains, suggesting a role for Hsc70 in scanning the infected nucleus for misfolded proteins. During 42°C heat shock, Hsc70 is redistributed from VICE domains into RC perhaps to remodel viral replication and regulatory proteins that have become insoluble in these compartments. The experiments presented in this paper suggest that VICE domains are nuclear protein quality control centers that are modified by HSV-1 to promote productive infection. Protein quality control is a protective cellular mechanism by which damaged proteins are refolded or degraded so that they cannot interfere with essential cellular processes. In the event that protein quality control machinery cannot refold or degrade damaged proteins, sequestration of misfolded protein is an alternative protective mechanism for reducing the toxic effects of misfolded protein. Several neurological diseases result from the accumulation of toxic misfolded proteins that cannot be efficiently refolded or degraded. In neurons from patients afflicted with Huntington's disease, misfolded huntingtin protein is sequestered in large aggregates in the nucleus called inclusion bodies. Inclusion bodies also contain protein quality control machinery including molecular chaperones, the proteasome and ubiquitin. Here we report that analogous structures called Virus-Induced Chaperone-Enriched (VICE) domains form in the nucleus of cells infected with Herpes Simplex Virus type 1 (HSV-1). VICE domains contain misfolded protein, chaperones and protein degradation activity. VICE domain formation is efficient in infected cells taxed with high levels of viral protein production. We hypothesize that misfolded proteins that arise in HSV-1-infected cells are sequestered in VICE domains to promote remodeling of misfolded proteins.