Species-specific IL-1β is an inflammatory sensor of Seneca Valley Virus 3C Protease

Inflammasomes play pivotal roles in inflammation by processing and promoting the secretion of IL-1β. Caspase-1 is involved in the maturation of IL-1β and IL-18, while human caspase-4 specifically processes IL-18. Recent structural studies of caspase-4 bound to Pro-IL-18 reveal the molecular basis of...

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Published inPLoS pathogens Vol. 20; no. 7; p. e1012398
Main Authors Huang, Xiangyu, Zhao, Zhenchao, Zhu, Cheng, Chai, Lvye, Yan, Ya, Yuan, Ye, Wu, Lei, Li, Minjie, Jiang, Xiaohan, Wang, Haiwei, Liu, Zheng, Li, Pingwei, Li, Xin
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 01.07.2024
Public Library of Science (PLoS)
Subjects
3C Viral Proteases - metabolism
Alveoli
Animals
Biology and Life Sciences
Caspase-1
Caspase-4
Cell culture
Cell death
Chromatography
Cleavage
Cysteine Endopeptidases - metabolism
Enzymes
Humans
Hydrophobicity
IL-1β
Infections
Inflammasomes
Inflammasomes - metabolism
Inflammation
Inflammation - metabolism
Interleukin 18
Interleukin-1beta - metabolism
Macrophages
Macrophages, Alveolar - metabolism
Macrophages, Alveolar - virology
Medicine and Health Sciences
Molecular modelling
Morphology
Mutagenesis
Picornaviridae
Picornaviridae Infections - metabolism
Picornaviridae Infections - virology
Plasmids
Protease
Proteinase
Research and Analysis Methods
Species Specificity
Substrates
Swine
Viral infections
Viral Proteins - metabolism
Viruses
Online AccessGet full text

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Abstract Inflammasomes play pivotal roles in inflammation by processing and promoting the secretion of IL-1β. Caspase-1 is involved in the maturation of IL-1β and IL-18, while human caspase-4 specifically processes IL-18. Recent structural studies of caspase-4 bound to Pro-IL-18 reveal the molecular basis of Pro-IL-18 activation by caspase-4. However, the mechanism of caspase-1 processing of pro-IL-1β and other IL-1β-converting enzymes remains elusive. Here, we observed that swine Pro-IL-1β (sPro-IL-1β) exists as an oligomeric precursor unlike monomeric human Pro-IL-1β (hPro-IL-1β). Interestingly, Seneca Valley Virus (SVV) 3C protease cleaves sPro-IL-1β to produce mature IL-1β, while it cleaves hPro-IL-1β but does not produce mature IL-1β in a specific manner. When the inflammasome is blocked, SVV 3C continues to activate IL-1β through direct cleavage in porcine alveolar macrophages (PAMs). Through molecular modeling and mutagenesis studies, we discovered that the pro-domain of sPro-IL-1β serves as an ’exosite’ with its hydrophobic residues docking into a positively charged 3C protease pocket, thereby directing the substrate to the active site. The cleavage of sPro-IL-1β generates a monomeric and active form of IL-1β, initiating the downstream signaling. Thus, these studies provide IL-1β is an inflammatory sensor that directly detects viral protease through an independent pathway operating in parallel with host inflammasomes.
AbstractList Inflammasomes play pivotal roles in inflammation by processing and promoting the secretion of IL-1β. Caspase-1 is involved in the maturation of IL-1β and IL-18, while human caspase-4 specifically processes IL-18. Recent structural studies of caspase-4 bound to Pro-IL-18 reveal the molecular basis of Pro-IL-18 activation by caspase-4. However, the mechanism of caspase-1 processing of pro-IL-1β and other IL-1β-converting enzymes remains elusive. Here, we observed that swine Pro-IL-1β (sPro-IL-1β) exists as an oligomeric precursor unlike monomeric human Pro-IL-1β (hPro-IL-1β). Interestingly, Seneca Valley Virus (SVV) 3C protease cleaves sPro-IL-1β to produce mature IL-1β, while it cleaves hPro-IL-1β but does not produce mature IL-1β in a specific manner. When the inflammasome is blocked, SVV 3C continues to activate IL-1β through direct cleavage in porcine alveolar macrophages (PAMs). Through molecular modeling and mutagenesis studies, we discovered that the pro-domain of sPro-IL-1β serves as an ’exosite’ with its hydrophobic residues docking into a positively charged 3C protease pocket, thereby directing the substrate to the active site. The cleavage of sPro-IL-1β generates a monomeric and active form of IL-1β, initiating the downstream signaling. Thus, these studies provide IL-1β is an inflammatory sensor that directly detects viral protease through an independent pathway operating in parallel with host inflammasomes.
Inflammasomes play pivotal roles in inflammation by processing and promoting the secretion of IL-1β. Caspase-1 is involved in the maturation of IL-1β and IL-18, while human caspase-4 specifically processes IL-18. Recent structural studies of caspase-4 bound to Pro-IL-18 reveal the molecular basis of Pro-IL-18 activation by caspase-4. However, the mechanism of caspase-1 processing of pro-IL-1β and other IL-1β-converting enzymes remains elusive. Here, we observed that swine Pro-IL-1β (sPro-IL-1β) exists as an oligomeric precursor unlike monomeric human Pro-IL-1β (hPro-IL-1β). Interestingly, Seneca Valley Virus (SVV) 3C protease cleaves sPro-IL-1β to produce mature IL-1β, while it cleaves hPro-IL-1β but does not produce mature IL-1β in a specific manner. When the inflammasome is blocked, SVV 3C continues to activate IL-1β through direct cleavage in porcine alveolar macrophages (PAMs). Through molecular modeling and mutagenesis studies, we discovered that the pro-domain of sPro-IL-1β serves as an 'exosite' with its hydrophobic residues docking into a positively charged 3C protease pocket, thereby directing the substrate to the active site. The cleavage of sPro-IL-1β generates a monomeric and active form of IL-1β, initiating the downstream signaling. Thus, these studies provide IL-1β is an inflammatory sensor that directly detects viral protease through an independent pathway operating in parallel with host inflammasomes.Inflammasomes play pivotal roles in inflammation by processing and promoting the secretion of IL-1β. Caspase-1 is involved in the maturation of IL-1β and IL-18, while human caspase-4 specifically processes IL-18. Recent structural studies of caspase-4 bound to Pro-IL-18 reveal the molecular basis of Pro-IL-18 activation by caspase-4. However, the mechanism of caspase-1 processing of pro-IL-1β and other IL-1β-converting enzymes remains elusive. Here, we observed that swine Pro-IL-1β (sPro-IL-1β) exists as an oligomeric precursor unlike monomeric human Pro-IL-1β (hPro-IL-1β). Interestingly, Seneca Valley Virus (SVV) 3C protease cleaves sPro-IL-1β to produce mature IL-1β, while it cleaves hPro-IL-1β but does not produce mature IL-1β in a specific manner. When the inflammasome is blocked, SVV 3C continues to activate IL-1β through direct cleavage in porcine alveolar macrophages (PAMs). Through molecular modeling and mutagenesis studies, we discovered that the pro-domain of sPro-IL-1β serves as an 'exosite' with its hydrophobic residues docking into a positively charged 3C protease pocket, thereby directing the substrate to the active site. The cleavage of sPro-IL-1β generates a monomeric and active form of IL-1β, initiating the downstream signaling. Thus, these studies provide IL-1β is an inflammatory sensor that directly detects viral protease through an independent pathway operating in parallel with host inflammasomes.
Inflammasomes play pivotal roles in inflammation by processing and promoting the secretion of IL-1β. Caspase-1 is involved in the maturation of IL-1β and IL-18, while human caspase-4 specifically processes IL-18. Recent structural studies of caspase-4 bound to Pro-IL-18 reveal the molecular basis of Pro-IL-18 activation by caspase-4. However, the mechanism of caspase-1 processing of pro-IL-1β and other IL-1β-converting enzymes remains elusive. Here, we observed that swine Pro-IL-1β (sPro-IL-1β) exists as an oligomeric precursor unlike monomeric human Pro-IL-1β (hPro-IL-1β). Interestingly, Seneca Valley Virus (SVV) 3C protease cleaves sPro-IL-1β to produce mature IL-1β, while it cleaves hPro-IL-1β but does not produce mature IL-1β in a specific manner. When the inflammasome is blocked, SVV 3C continues to activate IL-1β through direct cleavage in porcine alveolar macrophages (PAMs). Through molecular modeling and mutagenesis studies, we discovered that the pro-domain of sPro-IL-1β serves as an ’exosite’ with its hydrophobic residues docking into a positively charged 3C protease pocket, thereby directing the substrate to the active site. The cleavage of sPro-IL-1β generates a monomeric and active form of IL-1β, initiating the downstream signaling. Thus, these studies provide IL-1β is an inflammatory sensor that directly detects viral protease through an independent pathway operating in parallel with host inflammasomes. IL-1β is a key inflammatory mediator, crucial for immune responses and pathological inflammation. Upon the assembly of large complexes by NOD-like receptors, caspase-1 serves as the endogenous enzyme that cleaves Pro-IL-1β in activate IL-1β. Previous studies have identified IL-1β is an innate immune sensor of group A Streptococcus (GAS) protease SpeB. However, whether IL-1β is an inflammatory sensor for viral proteases remains unclear. Here, we report that Seneca Valley Virus (SVV) 3C protease functions as an unconventional IL-1β-converting enzyme (ICE), specifically and directly cleaving and processing swine Pro-IL-1β but not human Pro-IL-1β. The cleaved IL-1β is bioactive, consistent with the function of mature IL-1β. This finding reveals a novel virus-mediated activation mechanism of IL-1β and may influence the host’s inflammatory response.
Author Yuan, Ye
Zhu, Cheng
Huang, Xiangyu
Li, Xin
Yan, Ya
Li, Pingwei
Chai, Lvye
Jiang, Xiaohan
Zhao, Zhenchao
Wang, Haiwei
Wu, Lei
Liu, Zheng
Li, Minjie
AuthorAffiliation 6 Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas, United States of America
4 State Key Laboratory of Animal Disease Control, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
Stanford University, UNITED STATES OF AMERICA
1 National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China
2 Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, China
3 Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Tianjin University, Tianjin, China
5 Koblika Institute of Innovative Drug Discovery, School of Medicine, Chinese University of Hong Kong, Shenzhen, Guangdong, China
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– name: Stanford University, UNITED STATES OF AMERICA
– name: 5 Koblika Institute of Innovative Drug Discovery, School of Medicine, Chinese University of Hong Kong, Shenzhen, Guangdong, China
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CitedBy_id crossref_primary_10_1016_j_ijbiomac_2025_141587
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Snippet Inflammasomes play pivotal roles in inflammation by processing and promoting the secretion of IL-1β. Caspase-1 is involved in the maturation of IL-1β and...
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StartPage e1012398
SubjectTerms 3C Viral Proteases - metabolism
Alveoli
Animals
Biology and Life Sciences
Caspase-1
Caspase-4
Cell culture
Cell death
Chromatography
Cleavage
Cysteine Endopeptidases - metabolism
Enzymes
Humans
Hydrophobicity
IL-1β
Infections
Inflammasomes
Inflammasomes - metabolism
Inflammation
Inflammation - metabolism
Interleukin 18
Interleukin-1beta - metabolism
Macrophages
Macrophages, Alveolar - metabolism
Macrophages, Alveolar - virology
Medicine and Health Sciences
Molecular modelling
Morphology
Mutagenesis
Picornaviridae
Picornaviridae Infections - metabolism
Picornaviridae Infections - virology
Plasmids
Protease
Proteinase
Research and Analysis Methods
Species Specificity
Substrates
Swine
Viral infections
Viral Proteins - metabolism
Viruses
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Title Species-specific IL-1β is an inflammatory sensor of Seneca Valley Virus 3C Protease
URI https://www.ncbi.nlm.nih.gov/pubmed/39038050
https://www.proquest.com/docview/3086958595
https://www.proquest.com/docview/3083670971
https://pubmed.ncbi.nlm.nih.gov/PMC11293702
https://doaj.org/article/22ef453e94bc4d4cbee1680e300656b8
http://dx.doi.org/10.1371/journal.ppat.1012398
Volume 20
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