PMID- 37671864
OWN - NLM
STAT- MEDLINE
DCOM- 20231005
LR  - 20231008
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 97
IP  - 9
DP  - 2023 Sep 28
TI  - Human herpesvirus 6A nuclear matrix protein U37 interacts with heat shock 
      transcription factor 1 and activates the heat shock response.
PG  - e0071823
LID - 10.1128/jvi.00718-23 [doi]
LID - e00718-23
AB  - Nascent nucleocapsids of herpesviruses acquire a primary envelope during their 
      nuclear export by budding through the inner nuclear membrane into the perinuclear 
      space between the inner and outer nuclear membranes. This process is mediated by 
      a conserved viral heterodimeric complex designated the nuclear egress complex, 
      which consists of the nuclear matrix protein and the nuclear membrane protein. In 
      addition to its essential roles during nuclear egress, the nuclear matrix protein 
      has been shown to interact with intracellular signaling pathway molecules 
      including NF-kappaB and IFN-beta to affect viral or cellular gene expression. The human 
      herpesvirus 6A (HHV-6A) U37 gene encodes a nuclear matrix protein, the role of 
      which has not been analyzed. Here, we show that HHV-6A U37 activates the heat 
      shock element promoter and induces the accumulation of the molecular chaperone 
      Hsp90. Mechanistically, HHV-6A U37 interacts with heat shock transcription factor 
      1 (HSF1) and induces its phosphorylation at Ser-326. We report that 
      pharmacological inhibition of HSF1, Hsp70, or Hsp90 decreases viral protein 
      accumulation and viral replication. Taken together, our results lead us to 
      propose a model in which HHV-6A U37 activates the heat shock response to support 
      viral gene expression and replication. IMPORTANCE Human herpesvirus 6A (HHV-6A) 
      is a dsDNA virus belonging to the Roseolovirus genus within the Betaherpesvirinae 
      subfamily. It is frequently found in patients with neuroinflammatory disease, 
      although its pathogenetic role, if any, awaits elucidation. The heat shock 
      response is important for cell survival under stressful conditions that disrupt 
      homeostasis. Our results indicate that HHV-6A U37 activates the heat shock 
      element promoter and leads to the accumulation of heat shock proteins. Next, we 
      show that the heat shock response is important for viral replication. Overall, 
      our findings provide new insights into the function of HHV-6A U37 in host cell 
      signaling and identify potential cellular targets involved in HHV-6A pathogenesis 
      and replication.
FAU - Huang, Jing Rin
AU  - Huang JR
AD  - Division of Clinical Virology, Center for Infectious Diseases, Kobe University 
      Graduate School of Medicine , Kobe, Hyogo, Japan.
FAU - Arii, Jun
AU  - Arii J
AUID- ORCID: 0000-0002-1689-4016
AD  - Division of Clinical Virology, Center for Infectious Diseases, Kobe University 
      Graduate School of Medicine , Kobe, Hyogo, Japan.
FAU - Hirai, Mansaku
AU  - Hirai M
AD  - Division of Clinical Virology, Center for Infectious Diseases, Kobe University 
      Graduate School of Medicine , Kobe, Hyogo, Japan.
FAU - Nishimura, Mitsuhiro
AU  - Nishimura M
AD  - Division of Clinical Virology, Center for Infectious Diseases, Kobe University 
      Graduate School of Medicine , Kobe, Hyogo, Japan.
FAU - Mori, Yasuko
AU  - Mori Y
AD  - Division of Clinical Virology, Center for Infectious Diseases, Kobe University 
      Graduate School of Medicine , Kobe, Hyogo, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230906
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (Heat Shock Transcription Factors)
RN  - 0 (Viral Matrix Proteins)
RN  - 0 (HSF1 protein, human)
RN  - 0 (HSP90 Heat-Shock Proteins)
RN  - 0 (HSP70 Heat-Shock Proteins)
SB  - IM
MH  - Humans
MH  - *Heat Shock Transcription Factors/metabolism
MH  - *Heat-Shock Response/genetics
MH  - *Herpesvirus 6, Human/metabolism/pathogenicity
MH  - *Viral Matrix Proteins/metabolism
MH  - HSP90 Heat-Shock Proteins/metabolism
MH  - HSP70 Heat-Shock Proteins/metabolism
MH  - Promoter Regions, Genetic
MH  - Virus Replication
MH  - Phosphorylation
MH  - Gene Expression Regulation, Viral
MH  - Signal Transduction
PMC - PMC10537701
OTO - NOTNLM
OT  - HHV-6
OT  - HSP
OT  - heat shock response
OT  - herpesviruses
OT  - nuclear egress
COIS- The authors declare no conflict of interest.
EDAT- 2023/09/06 12:42
MHDA- 2023/10/04 06:43
PMCR- 2023/09/28
CRDT- 2023/09/06 09:03
PHST- 2023/10/04 06:43 [medline]
PHST- 2023/09/06 12:42 [pubmed]
PHST- 2023/09/06 09:03 [entrez]
PHST- 2023/09/28 00:00 [pmc-release]
AID - 00718-23 [pii]
AID - jvi.00718-23 [pii]
AID - 10.1128/jvi.00718-23 [doi]
PST - ppublish
SO  - J Virol. 2023 Sep 28;97(9):e0071823. doi: 10.1128/jvi.00718-23. Epub 2023 Sep 6.