Protein kinase D1 regulates innate immune signaling pathways to promote hepatitis C virus replication
- 1Department of Immunology and Immune Therapeutics, University of Southern California, Keck School of Medicine, Los Angeles, California, USA
Abstract
Hepatitis C virus (HCV) has developed multiple means to disrupt host innate immune response to promote its replication. Protein kinase D1 (PKD1) is a serine/threonine kinase involved in cell proliferation and lipid metabolism. By analyzing the effect of PKD1 on HCV replication, we found that HCV activated PKD1 via protein kinase C (PKC) early in infection and induced the cleavage of PKD1 at later timepoints of infection via caspase-3. PKD1 silencing had no effect on HCV entry, but it reduced HCV RNA levels in cells, indicating an important role of PKD1 in promoting HCV replication. PKD1 silencing also induced the expression of interferons (IFNs) and IFN-stimulated genes (ISGs) and augmented the HCV-induced TNF-α expression, which enhanced the IFN response. Interestingly, the induction of inflammasomes was compromised in HCV-infected cells in the absence of PKD1, indicating an important role of PKD1 in promoting the inflammasomal response. Taken together, our results indicated that HCV activated PKD1 to suppress the IFN response and TNF-α signaling and in the meantime induce the inflammasomal response. Our results, thus, revealed an interesting interplay between HCV and host innate immune responses and an important role of PKD1 in this intricate interplay.
IMPORTANCE: Hepatitis C virus (HCV) establishes chronic infection in most patients that it infects, and this chronic infection can lead to severe liver diseases including steatosis, cirrhosis, and hepatocellular carcinoma. PKD1 is a multifunctional protein that regulates lipid metabolism, cell proliferation, and cellular apoptosis. In this report, we investigated the relationship between HCV and PKD1. We found that HCV could activate PKD1 to suppress interferon response and TNF-α signaling to promote its replication and in the meantime enhance the inflammasomal response. These effects of HCV on PKD1 provide important insights for understanding the mechanism of HCV persistence and pathogenesis in patients.
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BibTeX
@article{lee2026protein,
title = {{Protein kinase D1 regulates innate immune signaling pathways to promote hepatitis C virus replication}},
author = {Jiyoung Lee and Yu-Chen Chuang and Johanna Ahn Lee and J.-H. James Ou},
journal = {Journal of Virology},
year = {2026},
month = sep,
doi = {10.1128/jvi.00693-26},
url = {https://doi.org/10.1128/jvi.00693-26},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Protein kinase D1 regulates innate immune signaling pathways to promote hepatitis C virus replication
AU - Jiyoung Lee
AU - Yu-Chen Chuang
AU - Johanna Ahn Lee
AU - J.-H. James Ou
PY - 2026
DA - 2026/09/09
JO - Journal of Virology
DO - 10.1128/jvi.00693-26
UR - https://doi.org/10.1128/jvi.00693-26
AB - Hepatitis C virus (HCV) has developed multiple means to disrupt host innate immune response to promote its replication. Protein kinase D1 (PKD1) is a serine/threonine kinase involved in cell proliferation and lipid metabolism. By analyzing the effect of PKD1 on HCV replication, we found that HCV activated PKD1 via protein kinase C (PKC) early in infection and induced the cleavage of PKD1 at later timepoints of infection via caspase-3. PKD1 silencing had no effect on HCV entry, but it reduced HCV RNA levels in cells, indicating an important role of PKD1 in promoting HCV replication. PKD1 silencing also induced the expression of interferons (IFNs) and IFN-stimulated genes (ISGs) and augmented the HCV-induced TNF-α expression, which enhanced the IFN response. Interestingly, the induction of inflammasomes was compromised in HCV-infected cells in the absence of PKD1, indicating an important role of PKD1 in promoting the inflammasomal response. Taken together, our results indicated that HCV activated PKD1 to suppress the IFN response and TNF-α signaling and in the meantime induce the inflammasomal response. Our results, thus, revealed an interesting interplay between HCV and host innate immune responses and an important role of PKD1 in this intricate interplay. IMPORTANCE: Hepatitis C virus (HCV) establishes chronic infection in most patients that it infects, and this chronic infection can lead to severe liver diseases including steatosis, cirrhosis, and hepatocellular carcinoma. PKD1 is a multifunctional protein that regulates lipid metabolism, cell proliferation, and cellular apoptosis. In this report, we investigated the relationship between HCV and PKD1. We found that HCV could activate PKD1 to suppress interferon response and TNF-α signaling to promote its replication and in the meantime enhance the inflammasomal response. These effects of HCV on PKD1 provide important insights for understanding the mechanism of HCV persistence and pathogenesis in patients.
SN - 0022-538X
SN - 1098-5514
ER -