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Region-specific innate antiviral responses of the human epididymis.

ABSTRACT: Viral infections of the epididymis are associated with epididymitis, which damages the epithelium and impairs fertility. We showed previously that innate immune response genes were differentially expressed in the corpus and cauda region of the human epididymis in comparison to the caput. Here we investigate the antiviral defense response mechanisms of human epididymis epithelial (HEE) cells. Toll-like receptor (TLR) 3 and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are enriched in HEE cells from the corpus and cauda region. These HEE cells show an enhanced response to antiviral ligands (poly(I:C) and HSV-60), as shown by increased IFN-? mRNA expression and IFN-? secretion. Nuclear translocation of phosphorylated p65 occurs after poly(I:C) exposure. In addition, paired box 2 (PAX2), which was implicated in regulating antiviral response pathways, is required for basal expression of the DNA sensor, Z-DNA binding protein (ZBP1) and type I interferon, in caput but not in cauda cells.

SUBMITTER: Browne JA

PROVIDER: S-EPMC6045438 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Region-specific innate antiviral responses of the human epididymis.

Browne James A JA Leir Shih-Hsing SH Eggener Scott E SE Harris Ann A

Molecular and cellular endocrinology 20180113

Viral infections of the epididymis are associated with epididymitis, which damages the epithelium and impairs fertility. We showed previously that innate immune response genes were differentially expressed in the corpus and cauda region of the human epididymis in comparison to the caput. Here we investigate the antiviral defense response mechanisms of human epididymis epithelial (HEE) cells. Toll-like receptor (TLR) 3 and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are enriched ...[more]

PMID: 29339104

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Project description:Elaborate regulation of innate immunity is necessary for the host to effectively respond to invading pathogens. As an important component of antiviral immunity transcription factors, the stability and activity of interferon (IFN) regulatory factor 3 (IRF3) are tightly controlled via multiple post-translational modifications. Here, we identified a human ovarian tumor domain-containing deubiquitinase OTUD6B as a positive regulator of IRF3 that facilitates type I IFN innate antiviral immune signaling. Mechanically, we found that OTUD6B interacts with IRF3 and directly hydrolyzes both the lysine 11 (K11)- and the lysine 33 (K33)-linked polyubiquitin chain, but only K33-linked polyubiquitin at Lys315 of IRF3 is responsible for IRF3 proteasome degradation. Notably, OTUD6B enhanced cellular antiviral responses in vivo, as evidenced by mice that overexpressed human OTUD6B were more resistant to RNA virus infection and had reduced viral load and morbidity. These findings revealed a previously unknown role for OTUD6B in the regulation of innate antiviral immunity and may provide a potential target for enhancing host antiviral defense. IMPORTANCE Interferon (IFN) regulatory factor (IRF3) is one of the key factors for type I IFN transcription. To sophisticatedly regulate type I IFN antiviral immune response, IRF3 activity is closely controlled by a variety of post-translational modifications. However, the regulatory mechanisms are still not fully elucidated. In the present study, we found that human deubiquitinase OTUD6B positively regulates IRF3-mediated antiviral immune response. OTUD6B can stabilize the IRF3 protein level via hydrolyzing (Lys33)-linked polyubiquitin at Lys315. More importantly, mice with OTUD6B overexpression exhibited more resistance to RNA virus infection. Thus, unlike the previous report that zebrafish OTUD6B negatively regulates the antiviral response by suppressing K63-linked ubiquitination of IRF3 and IRF7, we demonstrate that human OTUD6B actually enhances type I IFN response and has the potential for antiviral therapy.

Dataset Information

Region-specific innate antiviral responses of the human epididymis.

Publications

Region-specific innate antiviral responses of the human epididymis.

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