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.
Highlights
Protein quality control (PQC) is essential for maintaining active and properly folded proteins and for degrading aberrantly folded proteins that would otherwise interfere with vital cellular processes
We previously reported that Virus-Induced Chaperone-Enriched (VICE) domains are detected adjacent to prereplicative sites in cells in which replication compartments (RC) formation has been inhibited by drugs or infection with mutant viruses [21]
Vero cells were infected for various times at an MOI of 10, and cell lysates were assayed for expression of immediate-early (ICP4), early (ICP8) and late viral proteins and fixed cells were examined for RC formation (Figure 1A and 1B)
Summary
Protein quality control (PQC) is essential for maintaining active and properly folded proteins and for degrading aberrantly folded proteins that would otherwise interfere with vital cellular processes. PQC systems consist of a balance between protein refolding machinery (molecular chaperones) and protein degradation machinery (the 26S proteasomal system, ubiquitin conjugation and deconjugation systems and proteasome-independent degradation systems) (reviewed in [1]). In diseased cells, misfolded proteins such as mutant huntingtin, mutant ataxin-1 and other abnormal or overexpressed proteins can be detected in nuclear inclusion bodies that contain molecular chaperones, the 20S proteasome, ubiquitin and sometimes PML [2,3,4,5,6,7,8,9,10]. Additional evidence for nuclear PQC includes the detection of proteolytic activity in nuclear foci under normal cell growth conditions suggesting that turnover of nuclear substrates takes place in specific areas of the nucleus [13]
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