PMID- 38088561
OWN - NLM
STAT- MEDLINE
DCOM- 20240130
LR  - 20240130
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 98
IP  - 1
DP  - 2024 Jan 23
TI  - Lactate-lactylation-HSPA6 axis promotes PRRSV replication by impairing IFN-beta 
      production.
PG  - e0167023
LID - 10.1128/jvi.01670-23 [doi]
LID - e01670-23
AB  - Lactate, traditionally considered a metabolic by-product, has recently been 
      identified as a substrate for the induction of lactylation, a newly identified 
      epigenetic modification that plays an important role in the regulation of host 
      gene expression. Our previous study showed that lactate levels were significantly 
      elevated in cells infected with the porcine reproductive and respiratory syndrome 
      virus (PRRSV), an Arterivirus that has devastated the swine industry worldwide 
      for over 30 years. However, the role of elevated lactate in PRRSV infections 
      remains unknown. In this study, we found that lactate was required for optimal 
      PRRSV proliferation, and PRRSV infection increased cellular lactylation in a 
      dose-dependent manner. Using the Cleavage Under Targets and Tagmentation 
      (CUT&Tag) combined with RNA sequencing (RNA-seq) to screen the downstream genes 
      regulated by lactylation in PRRSV-infected cells, we found that PRRSV-induced 
      lactylation activated the expression of heat shock 70 kDa protein 6 (HSPA6). 
      Follow-up experiments showed that HSPA6 is important for PRRSV proliferation by 
      negatively modulating interferon (IFN)-beta induction. Mechanistically, HSPA6 
      impeded the interaction between TNF-receptor-associated factor 3 (TRAF3) and 
      inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKKepsilon), thereby 
      hindering the production of IFN-beta. Taken together, these results indicate that 
      the activated lactate-lactylation-HSPA6 axis promotes viral growth by impairing 
      IFN-beta induction, providing new therapeutic targets for the prevention and control 
      of PRRSV infection. The results presented here also link lactylation to the virus 
      life cycle, improving our understanding of epigenetic regulation in viral 
      infection.IMPORTANCEAs a newly identified epigenetic modification, 
      lactate-induced lactylation has received attentions because it plays important 
      roles in gene expression and contributes to tumorigenesis and the innate immune 
      response. Previous studies showed that many viruses upregulate cellular lactate 
      levels; however, whether virus-elevated lactate induces lactylation and the 
      subsequent biological significance of the modification to viral infection have 
      not been reported. In this study, we demonstrated that porcine reproductive and 
      respiratory syndrome virus (PRRSV) infection induced cellular lactylation, which, 
      in turn, upregulated the expression of HSPA6, an IFN-negative regulator. We also 
      dissected the mechanism by which HSPA6 negatively regulates IFN-beta production. To 
      our knowledge, this is the first report to study virus-induced lactylation and 
      establish the relationship between lactylation and virus infection.
FAU - Pang, Yu
AU  - Pang Y
AUID- ORCID: 0000-0002-6844-6928
AD  - National Key Laboratory of Agricultural Microbiology, College of Veterinary 
      Medicine, Huazhong Agricultural University, Wuhan, China.
FAU - Zhou, Yanrong
AU  - Zhou Y
AD  - The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, 
      Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China.
FAU - Wang, Yucheng
AU  - Wang Y
AD  - The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, 
      Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China.
FAU - Fang, Liurong
AU  - Fang L
AUID- ORCID: 0000-0003-1406-6409
AD  - National Key Laboratory of Agricultural Microbiology, College of Veterinary 
      Medicine, Huazhong Agricultural University, Wuhan, China.
FAU - Xiao, Shaobo
AU  - Xiao S
AUID- ORCID: 0000-0003-0023-9188
AD  - National Key Laboratory of Agricultural Microbiology, College of Veterinary 
      Medicine, Huazhong Agricultural University, Wuhan, China.
LA  - eng
GR  - 32130103/MOST | National Natural Science Foundation of China (NSFC)/
GR  - 32002279/MOST | National Natural Science Foundation of China (NSFC)/
GR  - 2022YFD1800305/Ministry of Science and Technology of the People's Republic of 
      China (MOST)/
PT  - Journal Article
DEP - 20231213
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 33X04XA5AT (Lactic Acid)
SB  - IM
MH  - Animals
MH  - Epigenesis, Genetic
MH  - Gene Expression
MH  - *Lactic Acid/metabolism
MH  - *Porcine Reproductive and Respiratory Syndrome/virology
MH  - *Porcine respiratory and reproductive syndrome virus/physiology
MH  - Swine
MH  - Virus Replication
PMC - PMC10804950
OTO - NOTNLM
OT  - heat shock 70 kDa protein 6 (HSPA6)
OT  - interferon
OT  - lactate
OT  - lactylation
OT  - porcine reproductive and respiratory syndrome virus
COIS- The authors declare no conflict of interest.
EDAT- 2023/12/13 12:44
MHDA- 2024/01/24 06:43
PMCR- 2023/12/13
CRDT- 2023/12/13 09:07
PHST- 2024/01/24 06:43 [medline]
PHST- 2023/12/13 12:44 [pubmed]
PHST- 2023/12/13 09:07 [entrez]
PHST- 2023/12/13 00:00 [pmc-release]
AID - 01670-23 [pii]
AID - jvi.01670-23 [pii]
AID - 10.1128/jvi.01670-23 [doi]
PST - ppublish
SO  - J Virol. 2024 Jan 23;98(1):e0167023. doi: 10.1128/jvi.01670-23. Epub 2023 Dec 13.