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Published on: March 16, 2017
PDZK1 upregulates nitric oxide production through the PI3K/ERK2 pathway to inhibit porcine circovirus type 2
Haochun Pan1, Changchao Huan1, Wei Zhang1
1Institutes of Agricultural Science and Technology Development, Yangzhou University, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China; Key Laboratory of Avian Bioproduct Development, Ministry of Agriculture and Rural Affairs, Yangzhou 225009, Jiangsu, China; College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu, China.
Abstract:
Porcine circovirus type 2 (PCV2) is the causative agent of porcine circovirus-associated disease. Changes in host cell gene expression are induced by PCV2 infection. Here, we showed that porcine PDZ Domain-Containing 1 (PDZK1) expression was enhanced during PCV2 infection and that overexpression of PDZK1 inhibited the expression of PCV2 Cap protein. PCV2 genomic DNA copy number and viral titers were decreased in PDZK1-overexpressing PK-15B6 cells. PDZK1 knockdown enhanced the replication of PCV2. Overexpression of PDZK1 activated the phosphoinositide 3-kinase (PI3K)/ERK2 signaling pathway to enhance nitric oxide (NO) levels, while PDZK1 knockdown had the opposite effects. A PI3K inhibitor (LY294002) and a NO synthase inhibitor (L-NAME hydrochloride) decreased the activity of PDZK1 in restricting PCV2 replication. ERK2 knockdown enhanced the proliferation of PCV2 by decreasing levels of NO. Levels of interleukin (IL)- 4 mRNA were reduced in PDZK1 knockdown and ERK2 knockdown PK-15B6 cells. Increased IL-4 mRNA levels were unable to decrease NO production in PDZK1-overexpressing cells. Thus, we conclude that PDZK1 affected PCV2 replication by regulating NO production via PI3K/ERK2 signaling. PDZK1 affected IL-4 expression through the PI3K/ERK2 pathway, but PDZK1 modulation of PCV2 replication occurred independently of IL-4. Our results contribute to understanding the biological functions of PDZK1 and provide a theoretical basis for the pathogenic mechanisms of PCV2.
Insights
Porcine circovirus type 2 (PCV2) infection is impacted by PDZ Domain-Containing 1 (PDZK1). PDZK1 restricts PCV2 replication by enhancing nitric oxide (NO) via the PI3K/ERK2 pathway, independent of IL-4.
Area of Science:
- Veterinary Virology
- Molecular Biology
- Immunology
Background:
- Porcine circovirus type 2 (PCV2) causes significant swine disease.
- PCV2 infection alters host cell gene expression.
- The role of host factors in PCV2 pathogenesis requires further elucidation.
Purpose of the Study:
- To investigate the role of porcine PDZ Domain-Containing 1 (PDZK1) in PCV2 replication.
- To elucidate the molecular mechanisms by which PDZK1 influences PCV2 infection.
Main Methods:
- Overexpression and knockdown of PDZK1 in PK-15B6 cells.
- Quantification of PCV2 genomic DNA and viral titers.
- Analysis of the phosphoinositide 3-kinase (PI3K)/ERK2 signaling pathway and nitric oxide (NO) levels.
- Assessment of interleukin-4 (IL-4) mRNA expression.
Main Results:
- PDZK1 expression was enhanced during PCV2 infection.
- Overexpression of PDZK1 inhibited PCV2 replication, while PDZK1 knockdown enhanced it.
- PDZK1 activated the PI3K/ERK2 pathway, increasing NO production.
- PDZK1's restriction of PCV2 replication was independent of IL-4, despite affecting IL-4 expression.
Conclusions:
- PDZK1 plays a crucial role in restricting PCV2 replication.
- PDZK1 modulates PCV2 replication via the PI3K/ERK2 signaling pathway and nitric oxide (NO) production.
- PDZK1 influences IL-4 expression, but this is not the primary mechanism for its antiviral effect against PCV2.
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