HECT E3 Ubiquitin Ligase-Regulated Txnip Degradation Facilitates TLR2-Mediated Inflammation During Group A Streptococcal Infection
Thioredoxin-interacting protein (Txnip) inhibits the activity of thioredoxin (Trx) to modulate inflammatory responses. The burden of inflammation caused by microbial infection is strongly associated with disease severity; however, the role of Txnip in bacterial infection remains unclear. In Group A...
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| Format: | Article |
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Frontiers Media S.A.
2019-09-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.02147/full |
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| author | Po-Chun Tseng Po-Chun Tseng Chih-Feng Kuo Chih-Feng Kuo Miao-Huei Cheng Shu-Wen Wan Chiou-Feng Lin Chiou-Feng Lin Chih-Peng Chang Chih-Peng Chang Yee-Shin Lin Yee-Shin Lin Jiunn-Jong Wu Chi-Chen Huang Chia-Ling Chen Chia-Ling Chen |
| author_facet | Po-Chun Tseng Po-Chun Tseng Chih-Feng Kuo Chih-Feng Kuo Miao-Huei Cheng Shu-Wen Wan Chiou-Feng Lin Chiou-Feng Lin Chih-Peng Chang Chih-Peng Chang Yee-Shin Lin Yee-Shin Lin Jiunn-Jong Wu Chi-Chen Huang Chia-Ling Chen Chia-Ling Chen |
| author_sort | Po-Chun Tseng |
| collection | DOAJ |
| description | Thioredoxin-interacting protein (Txnip) inhibits the activity of thioredoxin (Trx) to modulate inflammatory responses. The burden of inflammation caused by microbial infection is strongly associated with disease severity; however, the role of Txnip in bacterial infection remains unclear. In Group A Streptococcus (GAS)-infected macrophages, Txnip was degraded independent of glucose consumption and streptococcal cysteine protease expression. Treatment with proteasome inhibitors reversed GAS-induced Txnip degradation. The activation of Toll-like receptor 2 (TLR2) initiated Txnip degradation, while no further Txnip degradation was observed in TLR2-deficient bone marrow-derived macrophages. NADPH oxidase-regulated NF-κB activation and pro-inflammatory activation were induced and accompanied by Txnip degradation during GAS infection. Silencing Txnip prompted TLR2-mediated inducible nitric oxide synthase (iNOS)/NO, TNF-α, and IL-6 production whereas the blockage of Txnip degradation by pharmacologically inhibiting the HECT E3 ubiquitin ligase with heclin and AMP-dependent protein kinase with dorsomorphin effectively reduced such effects. Our findings reveal that TLR2/NADPH oxidase-mediated Txnip proteasomal degradation facilitates pro-inflammatory cytokine production during GAS infection. |
| first_indexed | 2024-12-16T12:23:25Z |
| format | Article |
| id | doaj.art-599841857bc14fc6915fdfce92f87352 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-16T12:23:25Z |
| publishDate | 2019-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-599841857bc14fc6915fdfce92f873522022-12-21T22:31:54ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-09-011010.3389/fimmu.2019.02147453499HECT E3 Ubiquitin Ligase-Regulated Txnip Degradation Facilitates TLR2-Mediated Inflammation During Group A Streptococcal InfectionPo-Chun Tseng0Po-Chun Tseng1Chih-Feng Kuo2Chih-Feng Kuo3Miao-Huei Cheng4Shu-Wen Wan5Chiou-Feng Lin6Chiou-Feng Lin7Chih-Peng Chang8Chih-Peng Chang9Yee-Shin Lin10Yee-Shin Lin11Jiunn-Jong Wu12Chi-Chen Huang13Chia-Ling Chen14Chia-Ling Chen15School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, TaiwanDepartment of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, TaiwanSchool of Medicine, I-Shou University, Kaohsiung, TaiwanDepartment of Nursing, I-Shou University, Kaohsiung, TaiwanSchool of Medicine for International Students, College of Medicine, I-Shou University, Kaohsiung, TaiwanSchool of Medicine for International Students, College of Medicine, I-Shou University, Kaohsiung, TaiwanDepartment of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, TaiwanGraduate Institute of Medical Sciences, Taipei Medical University, Taipei, TaiwanDepartment of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, TaiwanCenter of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, TaiwanDepartment of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, TaiwanCenter of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, TaiwanDepartment of Biotechnology and Laboratory Science in Medicine, School of Biomedical Science and Engineering, National Yang-Ming University, Taipei, Taiwan0Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, TaiwanSchool of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan1Pulmonary Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, TaiwanThioredoxin-interacting protein (Txnip) inhibits the activity of thioredoxin (Trx) to modulate inflammatory responses. The burden of inflammation caused by microbial infection is strongly associated with disease severity; however, the role of Txnip in bacterial infection remains unclear. In Group A Streptococcus (GAS)-infected macrophages, Txnip was degraded independent of glucose consumption and streptococcal cysteine protease expression. Treatment with proteasome inhibitors reversed GAS-induced Txnip degradation. The activation of Toll-like receptor 2 (TLR2) initiated Txnip degradation, while no further Txnip degradation was observed in TLR2-deficient bone marrow-derived macrophages. NADPH oxidase-regulated NF-κB activation and pro-inflammatory activation were induced and accompanied by Txnip degradation during GAS infection. Silencing Txnip prompted TLR2-mediated inducible nitric oxide synthase (iNOS)/NO, TNF-α, and IL-6 production whereas the blockage of Txnip degradation by pharmacologically inhibiting the HECT E3 ubiquitin ligase with heclin and AMP-dependent protein kinase with dorsomorphin effectively reduced such effects. Our findings reveal that TLR2/NADPH oxidase-mediated Txnip proteasomal degradation facilitates pro-inflammatory cytokine production during GAS infection.https://www.frontiersin.org/article/10.3389/fimmu.2019.02147/fullgroup A StreptococcusTxnipTLR2itchubiquitination |
| spellingShingle | Po-Chun Tseng Po-Chun Tseng Chih-Feng Kuo Chih-Feng Kuo Miao-Huei Cheng Shu-Wen Wan Chiou-Feng Lin Chiou-Feng Lin Chih-Peng Chang Chih-Peng Chang Yee-Shin Lin Yee-Shin Lin Jiunn-Jong Wu Chi-Chen Huang Chia-Ling Chen Chia-Ling Chen HECT E3 Ubiquitin Ligase-Regulated Txnip Degradation Facilitates TLR2-Mediated Inflammation During Group A Streptococcal Infection Frontiers in Immunology group A Streptococcus Txnip TLR2 itch ubiquitination |
| title | HECT E3 Ubiquitin Ligase-Regulated Txnip Degradation Facilitates TLR2-Mediated Inflammation During Group A Streptococcal Infection |
| title_full | HECT E3 Ubiquitin Ligase-Regulated Txnip Degradation Facilitates TLR2-Mediated Inflammation During Group A Streptococcal Infection |
| title_fullStr | HECT E3 Ubiquitin Ligase-Regulated Txnip Degradation Facilitates TLR2-Mediated Inflammation During Group A Streptococcal Infection |
| title_full_unstemmed | HECT E3 Ubiquitin Ligase-Regulated Txnip Degradation Facilitates TLR2-Mediated Inflammation During Group A Streptococcal Infection |
| title_short | HECT E3 Ubiquitin Ligase-Regulated Txnip Degradation Facilitates TLR2-Mediated Inflammation During Group A Streptococcal Infection |
| title_sort | hect e3 ubiquitin ligase regulated txnip degradation facilitates tlr2 mediated inflammation during group a streptococcal infection |
| topic | group A Streptococcus Txnip TLR2 itch ubiquitination |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.02147/full |
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