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Mumps virus (MuV) is the causative agent of mumps, a common childhood illness characterized by fever and swelling of the salivary glands. Like other viral infections, a number of host proteins are thought to involve in MuV infection. We have shown the function of several host factors in MuV infection. The chaperone proteins, heat shock protein 70 (Hsp70) and Hsp90, interact with the P and L proteins that form the polymerase complex and function in the protein quality control of these viral proteins, and thus they are essential host factors in MuV RNA synthesis. The R2TP complex is a host factor that contributes to effective viral propagation by precise regulation of viral RNA synthesis and evasion of host immune responses, and Rab11 is a host factor involved in viral RNP trafficking to the plasma membrane. This article summarizes the functions of host factors involved in MuV infection based on our researches.

HSP90 is one of the major molecular chaperones whose expression level increases by environmental stresses. Even under normal conditions, HSP90 is a highly abundant cytosolic protein and is essential for cell viability. HSP90 is involved in the maintenance of appropriate folding and conformation of many cellular functional proteins. These "HSP90 client proteins" are associated with HSP90 and they include a wide variety of signal-transducing proteins that regulate cell growth and differentiation, such as protein kinases and steroid hormone receptors. HSP90 functions in an ATP-dependent manner with other molecular chaperones such as Cdc37 and FKBP52. An HSP90 inhibitor, geldanamycin, binds the ATP-binding pocket of HSP90 and specifically inhibits the essential ATPase activity of HSP90. Thus, treatment of cells with geldanamycin results in inactivation, destabilization, and degradation of HSP90 client proteins. Because HSP90 client proteins play important roles in the regulation of the cell cycle, cell growth, cell survival, apoptosis, and oncogenesis, geldanamycin obstructs the proliferation of cultured cancer cells and shows anti-cancer activity in experimental animals. Although the precise mechanism of the effect of HSP90 inhibitors on cancer cells remains to be clarified, HSP90 inhibitors will be potential and effective cancer chemotherapeutic drugs with a unique profile. In fact, a modified geldanamycin with lower toxicity, 17-allylaminogeldanamycin (17-AAG), has been examined in phase I clinic trials with encouraging results.

We report here that a highly toxic coplanar polychlorinated biphenyl (PCB), 3,3',4,4',5-pentachlorobiphenyl (PenCB) induces molecular chaperones, HSP70 and HSP90 in liver cytosol of rats. Male Wistar rats received PenCB in corn oil once at a dose of 25 mg/kg i.p. Pair-fed control groups were treated with the vehicle and given the amount of chow matched with that taken by the PenCB-treated animals, and free-fed controls were given the vehicle. The liver cytosolic HSP70 level in rats treated with PenCB was 5-fold higher than those in free-fed controls, though that for pair-fed controls was approximately 2-fold higher than that in free-fed controls. The liver cytosolic HSP90 alpha and HSP90 beta levels were also higher in PenCB-treated rats than in both control groups, but the induction extent was lesser than that for HSP70. Inductive effect on the chaperones was examined with a single different dose of PenCB 0, 0.5, 1.0, 5.0, 10 and 25 mg/kg. Marked induction of the HSP70 level was observed with a minimum dose of PenCB 0.5 mg/kg. The HSP90 alpha level was induced with PenCB-dose dependent manner although the HSP90 beta induction was greatest with a dose of PenCB 5.0 mg/kg. HSP70 and HSP90 are essential for cells under normal conditions and act as molecular chaperones. HSP90 is well known to modulate the function of sex steroid hormone or aromatic hydrocarbon receptors while HSP70 is required for receptor-HSP90 heterocomplex assembly. The role of molecular chaperones may be involved in the endocrine disrupting properties of coplanar PCB and dioxins.

Dysregulation in the negative feedback of the hypothalamus-pituitary-adrenal (HPA) system is observed in a subgroup of major depression. Recent studies have postulated that tricyclic antidepressant treatment increases the glucocorticoid receptor (GR) in the brain and that such GR up-regulation normalizes the hyperactivity of HPA systems. The GR is associated with heat-shock proteins (HSPs) as a functional complex with a high affinity for steroid binding. In this study, we have examined the effects of chronic fixed (restraint) stress (CFS) and chronic variable stress (CVS) on the subcellular localization of GR and HSP90 in rat hippocampus using an immunoblotting procedure. A single restraint stress for 1-2 h and a single treatment with dexamethasone (DEX) 0.5 mg/kg, s.c. induced a translocation of the cytosolic GR to nuclei. Long-term treatment with DEX 0.1 mg/kg, s.c. for 14 days caused a significant decrease in both cytosolic and nucleic GR. There was no significant change in either cytosolic or nucleic GR after CFS for 14 days. However, CVS for 14 days increased both cytosolic GRs and HSP90 while nucleic GR was not changed. CFS for 14 days had no influence on the DEX-induced translocation of GR to nuclei, whereas GR translocation by DEX was not observed after CVS for 14 days. Gel filtration chromatography of the hippocampal cytosol after CVS indicated an increase in monomeric GR (approximately 90 kDa) and a decrease in the GR-HSP complex (approximately 300 kDa). Since CVS has been reported to increase serum corticosterone in rats, our results suggest that CVS prevents formation of the GR-HSP complex. A new intracellular environment rather than excessive serum corticosterone caused by CVS may contribute to inhibition of the formation of GR-HSP complex. It is proposed that the CVS could be an appropriate model for disturbance in the negative feedback control of HPA systems.