Suppression of Thermotolerance in Mumps Virus-infected Cells Is Caused by Lack of HSP27 Induction Contributed by STAT-1

Abstract

Viral infection modulates the regulation of apoptosis in host cells. Here, we report a novel mechanism by which human cells infected with mumps virus become susceptible to apoptosis caused by extracellular stresses. Mumps virus stimulates proteasome-dependent degradation of STAT-1 by action of viral accessory protein V, resulting in a severe decrease in STAT-1 protein in infected cells. We exposed mumps virus-infected and uninfected cells to heat and chemical stress. The infected cells failed to acquire resistance to apoptotic stimuli (thermotolerance) after exposure to these mild stresses. The induction of HSP27 by stress exposure was dramatically suppressed in the infected cells, but HSP70 induction was not affected. STAT-1 was required for transcriptional activation of the HSP27 gene, but not for the HSP70 gene, and cDNA transfection of STAT-1 in mumps virus-infected cells restored thermotolerance. Phosphorylated heat shock factor-1 (HSF-1) and STAT-1 phosphorylated on neither tyrosine nor serine residues were co-transported to the nucleus in response to stress. Furthermore, overexpression of unphosphorylatable mutants of STAT-1 also restored thermotolerance in mumps virus-infected cells. These lines of evidence indicate that the induction of HSP27 by stress requires STAT-1 in addition to the activated HSF-1. Furthermore, STAT-1 required for the induction of HSP27 worked independent to its phosphorylation. Thus, HSP27-dependent thermotolerance is suppressed by mumps virus infection through the destruction of STAT-1. The lack of thermotolerance should allow the infected cells to be eliminated by apoptosis and might be a host defense against viral infection.

Basal and infection-induced levels of heat shock proteins in human aging

“…Hsp27 did not exhibit the same pattern of association in comparison to the other Hsp families, indicating different regulation mechanisms (Stephanou et al 1997;Cornelussen et al 2001;Yokota et al 2003). Indeed, Hsp27 levels did not alter considerably with the inflammatory indices.…”

Cellular responses to mild heat stress

“…Human cells infected with virus such as mumps virus were recently shown to be more susceptible to apoptosis caused by extracellular stresses. The susceptibility is due to suppression of HSP27-dependent thermotolerance by the viral accessory protein V-mediated destruction of STAT-1 [188]. STAT-1 is required for transcriptional activation of the HSP27 gene, but not for the HSP70 gene, in addition to the activated HSF1 [188].…”

“…The susceptibility is due to suppression of HSP27-dependent thermotolerance by the viral accessory protein V-mediated destruction of STAT-1 [188]. STAT-1 is required for transcriptional activation of the HSP27 gene, but not for the HSP70 gene, in addition to the activated HSF1 [188]. HSP70 and HSP27 have also been implicated in translational thermotolerance; heat stress results in inhibition of general protein 18 H. G. Park et al Cellular responses to mild heat stress synthesis and in thermotolerant cells, protein synthesis is still rapidly inhibited by heat stress, but recovers faster than in naive heat-shocked cells, a phenomenon known as translational thermotolerance.…”

Arsenite pre‐conditioning reduces UVB‐induced apoptosis in corneal epithelial cells through the anti‐apoptotic activity of 27 kDa heat shock protein (HSP27)

“…Finally, when intracellular HSP27 was neutralized by the internalized HSP27 antibody, the inhibition of UVBinduced apoptosis by arsenite condition was accordingly attenuated. Recently, Yokota et al (2003) infected cells with mumps virus to suppress HSP27, and they found that the infected cells that lacked HSP27 failed to acquire thermotolerance following exposure to the mild stresses.…”