Respiratory syncytial virus induces NRF2 degradation through a promyelocytic leukemia protein - ring finger protein 4 dependent pathway

被引:47
|
作者
Komaravelli, Narayana [1 ]
Ansar, Maria [4 ]
Garofalo, Roberto P. [1 ,2 ,3 ,4 ]
Casola, Antonella [1 ,2 ,3 ,4 ]
机构
[1] Univ Texas Med Branch Galveston, Dept Pediat, Galveston, TX USA
[2] Univ Texas Med Branch Galveston, Sealy Ctr Vaccine Dev, Galveston, TX USA
[3] Univ Texas Med Branch Galveston, Sealy Ctr Mol Med, Galveston, TX USA
[4] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA
关键词
Respiratory syncytial virus; Antioxidant enzymes; NRF2; SUMOylation; Ubiquitination; PML nuclear bodies; KEAP1; RNF4; TRANSCRIPTION FACTOR NRF2; ANTIOXIDANT RESPONSE; OXIDATIVE STRESS; GENE-EXPRESSION; ACTIVATION; INFECTION; CELLS; INTERFERON; HOSPITALIZATIONS; INDUCTION;
D O I
10.1016/j.freeradbiomed.2017.10.380
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Respiratory syncytial virus (RSV) is the most important cause of viral acute respiratory tract infections and hospitalizations in children, for which no vaccine or specific treatments are available. RSV causes airway mucosa inflammation and cellular oxidative damage by triggering production of reactive oxygen species and by inhibiting at the same time expression of antioxidant enzymes, via degradation of the transcription factor NF-E2-related factor 2 (NRF2). RSV infection induces NRF2 deacetylation, ubiquitination, and degradation through a proteasome-dependent pathway. Although degradation via KEAP1 is the most common mechanism, silencing KEAP1 expression did not rescue NRF2 levels during RSV infection. We found that RSV-induced NRF2 degradation occurs in an SUMO-specific E3 ubiquitin ligase - RING finger protein 4 (RNF4)-dependent manner. NRF2 is progressively SUMOylated in RSV infection and either blocking SUMOylation or silencing RNF4 expression rescued both NRF2 nuclear levels and transcriptional activity. RNF4 associates with promyelocytic leukemia - nuclear bodies (PML-NBs). RSV infection induces the expression of PML and PML-NBs formation in an interferon (INF)-dependent manner and also induces NRF2 - PMN-NBs association. Inhibition of PML-NB formation by blocking IFN pathway or silencing PML expression resulted in a significant reduction of RSV-associated NRF2 degradation and increased antioxidant enzyme expression, identifying the RNF4-PML pathway as a key regulator of antioxidant defenses in the course of viral infection.
引用
收藏
页码:494 / 504
页数:11
相关论文
共 50 条
  • [1] Respiratory Syncytial Virus Infection Downregulates Antioxidant Enzyme Expression by Triggering Nrf2 Degradation
    Komaravelli, Narayana
    Tiang, Bing
    Ivanciuc, Teodora
    Brasier, Allan
    Garofalo, Roberto
    Casola, Antonella
    FASEB JOURNAL, 2015, 29
  • [2] Respiratory Syncytial Virus Matrix Protein Induces Lung Epithelial Cell Cycle Arrest through a p53 Dependent Pathway
    Bian, Tao
    Gibbs, John D.
    Orvell, Claes
    Imani, Farhad
    PLOS ONE, 2012, 7 (05):
  • [3] Arkadia mediates sumoylation-dependent degradation of Nrf2 in promyelocytic leukemia-nuclear bodies
    McIntosh, Deneshia
    Arinze, Ifeanyi
    FASEB JOURNAL, 2014, 28 (01):
  • [4] Arkadia (RING Finger Protein 111) Mediates Sumoylation-Dependent Stabilization of Nrf2 Through K48-Linked Ubiquitination
    McIntosh, Deneshia J.
    Walters, Treniqka S.
    Arinze, Ifeanyi J.
    Davis, Jamaine S.
    CELLULAR PHYSIOLOGY AND BIOCHEMISTRY, 2018, 46 (01) : 418 - 430
  • [5] Arkadia (RING finger protein 111) mediates sumoylation-dependent stabilization of Nrf2 through K48-linked ubiquitylation
    Davis, Jamaine
    McIntosh, Deneshia
    Walters, Treniqka
    Arinze, Ifeanyi
    FASEB JOURNAL, 2018, 32 (01):
  • [6] Arkadia (RING finger protein 111) mediates sumoylation-dependent stabilization of Nrf2 through K48-linked ubiquitylation.
    McInstosh, D.
    Walters, T.
    Arinze, I.
    Davis, J. S.
    MOLECULAR BIOLOGY OF THE CELL, 2017, 28
  • [7] Arkadia (RING finger protein 111) mediates sumoylation-dependent stabilization of Nrf2 through K48-linked ubiquitylation.
    Davis, J. S.
    McInstosh, D.
    Walters, T.
    Arinze, I.
    MOLECULAR BIOLOGY OF THE CELL, 2018, 29 (26)
  • [8] Curcumin induces stabilization of Nrf2 protein through Keap1 cysteine modification
    Shin, Jun Wan
    Chun, Kyung-Soo
    Kim, Do-Hee
    Kim, Su-Jung
    Kim, Seong Hoon
    Cho, Nam-Chul
    Na, Hye-Kyung
    Surh, Young-Joon
    BIOCHEMICAL PHARMACOLOGY, 2020, 173
  • [9] Nonstructural Protein 1 of Tick-Borne Encephalitis Virus Induces Oxidative Stress and Activates Antioxidant Defense by the Nrf2/ARE Pathway
    Kuzmenko, Yulia V.
    Smirnova, Olga A.
    Ivanov, Alexander V.
    Starodubova, Elizaveta S.
    Karpov, Vadim L.
    INTERVIROLOGY, 2016, 59 (02) : 111 - 117
  • [10] Respiratory syncytial virus infection down-regulates antioxidant enzyme expression by triggering deacetylation-proteasomal degradation of Nrf2
    Komaravelli, Narayana
    Tian, Bing
    Ivanciuc, Teodora
    Mautemps, Nicholas
    Brasier, Allan R.
    Garofalo, Roberto P.
    Casola, Antonella
    FREE RADICAL BIOLOGY AND MEDICINE, 2015, 88 : 391 - 403