Is there a role for HSF1 in viral infections?

Abstract

Cells undergo numerous processes to adapt to new challenging conditions and stressors. Heat stress is regulated by a family of heat shock factors (HSFs) that initiate a heat shock response by upregulating the expression of heat shock proteins (HSPs) intended to counteract cellular damage elicited by increased environmental temperature. Heat shock factor 1 (HSF1) is known as the master regulator of the heat shock response and upon its activation induces the transcription of genes that encode for molecular chaperones, such as HSP40, HSP70, and HSP90. Importantly, an accumulating body of studies relates HSF1 with viral infections; the induction of fever during viral infection may activate HSF1 and trigger a consequent heat shock response. Here, we review the role of HSF1 in different viral infections and its impact on the health outcome for the host. Studying the relationship between HSF1 and viruses could open new potential therapeutic strategies given the availability of drugs that regulate the activation of this transcription factor.

Keywords: HSF1; heat shock; heat shock factor 1; stress; viral infections.

Fig. 1

HSF1 activation. HSF1 is usually present in the cell in an inactivated form. Inactivation of HSF1 occurs mainly by three mechanisms: (1a) HSP90 binding to HSF1, (1b) HSF1 stabilization through the formation of a leucine zipper structure within the protein (red lines), or (1c) through post‐transcriptional modifications, such as acetylation, sumoylation, and phosphorylation. (2) HSF1 is activated when an increase in misfolded proteins occurs in the cell, such as after heat shock (increased environmental temperature). HSF1 activation involves the release of monomeric HSF1 from chaperones, such as HSP20 and HSP90 (3a). Once activated, HSF1 monomers interact together to form a trimer that is stabilized by leucine zippers (red lines) (3b) and is phosphorylated by the calcium/calmodulin‐dependent protein kinase II gamma (CaMKIIγ). (4) HSPs act as molecular chaperones for the correct folding of numerous proteins in the cell. (5) HSF1 binds to DNA sequences in the genome, namely heat shock elements (HSE) in the promoters of genes encoding for heat shock responses, such as heat shock proteins (HSPs) promoting their transcription. HSF1 also promotes the transcription of genes involved in the regulation of apoptosis, DNA repair, modulation of drug resistance, unfolded protein response (UPR) at the endoplasmic reticulum, autophagy, and oxidative stress, among others. (6) Acetylation (blue circles) of HSF1 at Lys80 destabilizes its interaction with the DNA. HSP40 together with HSP70 bind to specific sites in HSF1 monomers leading to a destabilization of the trimer. (7) Excess HSF1 is degraded through the SCFβ‐TrCP pathway, and only a basal amount of inactive HSF1 remains in the cell.

Fig. 2

Schematic representations of the participation of HSF1 in viral infections. Red arrows indicate inhibitory pathways, while green arrows indicate activation pathways. From left to right: (1a) HSF1 associates with Nef, an early viral protein produced during HIV‐1 infection and (1b) activates HSP40, which promotes (1c) viral gene expression. (1d) HSF1 promotes the reactivation of HIV from latency, by binding to the 5'LTR in the viral genome and (1e) promotes the recruitment of protein complexes, such as p300. (1f) Additionally, HSF1 recruits p300 for self‐acetylation. (1g) HSF1 acts as a repressor in HIV‐induced inflammation, which occurs through a competition between HSF1 and nuclear factor κB (NF‐κB), which inhibits the NF‐κB pathway. (2a) HSF1 binds to ASPP2, which blocks the translocation of HSF1 to the nucleus and impairs Atg7 transcription, (2b) thus preventing autophagy and the replication of the hepatitis B virus (HBV) in hepatocytes. (3) HSF1 promotes autophagy through the transcription of Atg7 and inhibits dengue virus (DENV) replication. (4) HSF1 and heat shock proteins (HSPs), such as HSP90, HSP70, and other HSPs promote the replication of vaccinia virus (VACV). (5) Coxsackievirus B3 (CVB3) activates HSF1 and promotes the transcription of the gene of HSP70 through which downstream interactions promote viral replication. (6) There is a heat shock response element (HSE) in the viral genome of Epstein–Barr virus (EBV), specifically in the Qp gene. HSF1 binds to Qp promoting the initiation of viral replication in EBV‐infected cells. (7) The human cytomegalovirus (HCMV) promotes HSF1 activation to inhibit apoptosis, thus extending the lifespan of infected monocytes. (8) Finally, a constitutively active mutant of HSF1 (cHSF1) induces viral replication, and its overexpression induces a tumor‐specific immune response when using the oncolytic adenovirus Adel55.