Heat shock proteins and viral infection

Abstract

Heat shock proteins (HSPs) are a kind of proteins which mostly found in bacterial, plant and animal cells, in which they are involved in the monitoring and regulation of cellular life activities. HSPs protect other proteins under environmental and cellular stress by regulating protein folding and supporting the correctly folded structure of proteins as chaperones. During viral infection, some HSPs can have an antiviral effect by inhibiting viral proliferation through interaction and activating immune pathways to protect the host cell. However, although the biological function of HSPs is to maintain the homeostasis of cells, some HSPs will also be hijacked by viruses to help their invasion, replication, and maturation, thereby increasing the chances of viral survival in unfavorable conditions inside the host cell. In this review, we summarize the roles of the heat shock protein family in various stages of viral infection and the potential uses of these proteins in antiviral therapy.

Keywords: HSPs; chaperones; immunological pathways; protein folding; viral infection.

Figure 1

Molecular mechanisms of heat shock proteins induced under stress (A) Hsp27 binds to unfolded proteins that accumulate in the cytosol during stress, and then diverts unfolded proteins along the protein folding pathway, ultimately reaching HSP90. (B) In response to oxidative stress, the HSP60-10 complex helps to localize FHIT protein to the mitochondria, where it stabilizes ferredoxin reductase, leading to enhanced production of reactive oxygen species. This in turn triggers cytochrome c release and subsequent activation of the caspase cascade, ultimately causing apoptosis. (C) Following viral invasion, the RLR/MDA5 signaling pathway is activated. HSP27 can specifically stabilize MDA5 during expression to enhance the RLR/MDA5 signaling pathway. In mitochondria, HSP60 interacts with MAVS to increase MAVS-mediated IFN-β promoter activity and the transcriptional levels of IFN-β. Furthermore, it can upregulate MAVS-induced mRNA transcription of IFN-stimulated genes (ISGs). (D) Hsp104/ClpB complexes in host cells process disordered aggregates accumulated following cellular stress as well as ordered aggregates formed after prion infection with the help of the HSP70-40 partner system, dissociating them into component proteins and reactivating them.

Figure 2

Heat shock proteins and immunological pathways (A) HSP27 regulates the NF-κB pathway. In the NF-κB signaling pathway, nuclear factor κB mainly exists as a heterodimer of p65 and P50, and I-κBα is a major inhibitor of NF-κB, which combines with them to form a complex in the resting state. The dimers are held inactive in the cytoplasm by their interaction with I-kBα proteins. I-κBα is phosphorylated when stimulated by external signals, and after phosphorylation, I-κBα proteins undergo ubiquitin-dependent degradation by the proteasome, after which NF-κB is translocated to the nucleus, where it acts as a transcription factor. The interaction of HSP27 with the 26S proteasome is necessary for the degradation of phosphorylated I-κBα, and overexpression of HSP27 enhances the proteasomal degradation of phosphorylated I-κBα. (B) HSP70 negatively regulates NLRP3 inflammatory vesicles. After SARS-CoV infects cells, the virus envelope E protein triggers the activation of the NF-κB inflammatory signaling cascade, which activates the NLRP3 inflammasome. Activation of NLRP3 induces the maturation of caspase-1, which in turn activates the secretion of interleukins IL-1β and IL-18. While IL-1β is an important factor in inducing a rise in core body temperature, HSP70, produced in response to the heat shock factor 1 (HSF-1), reduces the inflammatory response blocking NLRP3 and the articulator ASC to induce caspase-1 precursor maturation following a rise in body temperature.