TNIK regulation of interferon signaling and endothelial cell response to virus infection

Khanh M. Chau; Abishai Dominic; Eleanor L. Davis; Sivareddy Kotla; Estefani Turcios Berrios; Arsany Fahim; Ashwin Arunesh; Shengyu Li; Dongyu Zhao; Kaifu Chen; Alan R. Davis; Minh T.H. Nguyen; Yongxing Wang; Scott E. Evans; Guangyu Wang; John P. Cooke; Jun Ichi Abe; David P. Huston; Nhat Tu Le

doi:10.3389/fcvm.2023.1213428

TNIK regulation of interferon signaling and endothelial cell response to virus infection

Khanh M. Chau, Abishai Dominic, Eleanor L. Davis, Sivareddy Kotla, Estefani Turcios Berrios, Arsany Fahim, Ashwin Arunesh, Shengyu Li, Dongyu Zhao, Kaifu Chen, Alan R. Davis, Minh T.H. Nguyen, Yongxing Wang, Scott E. Evans, Guangyu Wang, John P. Cooke, Jun Ichi Abe, David P. Huston, Nhat Tu Le

Research output: Contribution to journal › Article › peer-review

Abstract

BACKGROUND: Traf2 and Nck-interacting kinase (TNIK) is known for its regulatory role in various processes within cancer cells. However, its role within endothelial cells (ECs) has remained relatively unexplored.

METHODS: Leveraging RNA-seq data and Ingenuity Pathway Analysis (IPA), we probed the potential impact of TNIK depletion on ECs.

RESULTS: Examination of RNA-seq data uncovered more than 450 Differentially Expressed Genes (DEGs) in TNIK-depleted ECs, displaying a fold change exceeding 2 with a false discovery rate (FDR) below 0.05. IPA analysis unveiled that TNIK depletion leads to the inhibition of the interferon (IFN) pathway [-log ( p-value) >11], downregulation of IFN-related genes, and inhibition of Hypercytokinemia/Hyperchemokinemia [-log ( p-value) >8]. The validation process encompassed qRT-PCR to evaluate mRNA expression of crucial IFN-related genes, immunoblotting to gauge STAT1 and STAT2 protein levels, and ELISA for the quantification of IFN and cytokine secretion in siTNIK-depleted ECs. These assessments consistently revealed substantial reductions upon TNIK depletion. When transducing HUVECs with replication incompetent E1-E4 deleted adenovirus expressing green fluorescent protein (Ad-GFP), it was demonstrated that TNIK depletion did not affect the uptake of Ad-GFP. Nonetheless, TNIK depletion induced cytopathic effects (CPE) in ECs transduced with wild-type human adenovirus serotype 5 (Ad-WT).

SUMMARY: Our findings suggest that TNIK plays a crucial role in regulating the EC response to virus infections through modulation of the IFN pathway.

Original language	English (US)
Article number	1213428
Pages (from-to)	1213428
Journal	Frontiers in cardiovascular medicine
Volume	10
DOIs	https://doi.org/10.3389/fcvm.2023.1213428 https://doi.org/10.3389/fcvm.2023.1213428
State	Published - 2023

Keywords

interferons
RNA-Seq
STATs
TNIK
virus infection

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

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Chau, K. M., Dominic, A., Davis, E. L., Kotla, S., Berrios, E. T., Fahim, A., Arunesh, A., Li, S., Zhao, D., Chen, K., Davis, A. R., Nguyen, M. T. H., Wang, Y., Evans, S. E., Wang, G., Cooke, J. P., Abe, J. I., Huston, D. P., & Le, N. T. (2023). TNIK regulation of interferon signaling and endothelial cell response to virus infection. Frontiers in cardiovascular medicine, 10, 1213428. Article 1213428. https://doi.org/10.3389/fcvm.2023.1213428, https://doi.org/10.3389/fcvm.2023.1213428

Chau, KM, Dominic, A, Davis, EL, Kotla, S, Berrios, ET, Fahim, A, Arunesh, A, Li, S, Zhao, D, Chen, K, Davis, AR, Nguyen, MTH, Wang, Y, Evans, SE, Wang, G , Cooke, JP, Abe, JI, Huston, DP & Le, NT 2023, 'TNIK regulation of interferon signaling and endothelial cell response to virus infection', Frontiers in cardiovascular medicine, vol. 10, 1213428, pp. 1213428. https://doi.org/10.3389/fcvm.2023.1213428, https://doi.org/10.3389/fcvm.2023.1213428

@article{5afe44d4a5a04c3a9ebd74b9b994ec5d,

title = "TNIK regulation of interferon signaling and endothelial cell response to virus infection",

abstract = "BACKGROUND: Traf2 and Nck-interacting kinase (TNIK) is known for its regulatory role in various processes within cancer cells. However, its role within endothelial cells (ECs) has remained relatively unexplored.METHODS: Leveraging RNA-seq data and Ingenuity Pathway Analysis (IPA), we probed the potential impact of TNIK depletion on ECs.RESULTS: Examination of RNA-seq data uncovered more than 450 Differentially Expressed Genes (DEGs) in TNIK-depleted ECs, displaying a fold change exceeding 2 with a false discovery rate (FDR) below 0.05. IPA analysis unveiled that TNIK depletion leads to the inhibition of the interferon (IFN) pathway [-log ( p-value) >11], downregulation of IFN-related genes, and inhibition of Hypercytokinemia/Hyperchemokinemia [-log ( p-value) >8]. The validation process encompassed qRT-PCR to evaluate mRNA expression of crucial IFN-related genes, immunoblotting to gauge STAT1 and STAT2 protein levels, and ELISA for the quantification of IFN and cytokine secretion in siTNIK-depleted ECs. These assessments consistently revealed substantial reductions upon TNIK depletion. When transducing HUVECs with replication incompetent E1-E4 deleted adenovirus expressing green fluorescent protein (Ad-GFP), it was demonstrated that TNIK depletion did not affect the uptake of Ad-GFP. Nonetheless, TNIK depletion induced cytopathic effects (CPE) in ECs transduced with wild-type human adenovirus serotype 5 (Ad-WT). SUMMARY: Our findings suggest that TNIK plays a crucial role in regulating the EC response to virus infections through modulation of the IFN pathway.",

keywords = "interferons, RNA-Seq, STATs, TNIK, virus infection",

author = "Chau, {Khanh M.} and Abishai Dominic and Davis, {Eleanor L.} and Sivareddy Kotla and Berrios, {Estefani Turcios} and Arsany Fahim and Ashwin Arunesh and Shengyu Li and Dongyu Zhao and Kaifu Chen and Davis, {Alan R.} and Nguyen, {Minh T.H.} and Yongxing Wang and Evans, {Scott E.} and Guangyu Wang and Cooke, {John P.} and Abe, {Jun Ichi} and Huston, {David P.} and Le, {Nhat Tu}",

note = "Funding Information: This study was partially supported by funding from the National Institutes of Health (NIH) to JA, NTL, and JPC (HL149303 and HL163857), JA (AI156921), JPC (HL148338 and HL157790), and NTL (HL134740, HL157790). Acknowledgments Publisher Copyright: 2024 Chau, Dominic, Davis, Kotla, Berrios, Fahim, Arunesh, Li, Zhao, Chen, Davis, Nguyen, Wang, Evans, Wang, Cooke, Abe, Huston and Le.",

year = "2023",

doi = "10.3389/fcvm.2023.1213428",

language = "English (US)",

volume = "10",

pages = "1213428",

journal = "Frontiers in cardiovascular medicine",

issn = "2297-055X",

publisher = "Frontiers Media S. A.",

}

TY - JOUR

T1 - TNIK regulation of interferon signaling and endothelial cell response to virus infection

AU - Chau, Khanh M.

AU - Dominic, Abishai

AU - Davis, Eleanor L.

AU - Kotla, Sivareddy

AU - Berrios, Estefani Turcios

AU - Fahim, Arsany

AU - Arunesh, Ashwin

AU - Li, Shengyu

AU - Zhao, Dongyu

AU - Chen, Kaifu

AU - Davis, Alan R.

AU - Nguyen, Minh T.H.

AU - Wang, Yongxing

AU - Evans, Scott E.

AU - Wang, Guangyu

AU - Cooke, John P.

AU - Abe, Jun Ichi

AU - Huston, David P.

AU - Le, Nhat Tu

N1 - Funding Information: This study was partially supported by funding from the National Institutes of Health (NIH) to JA, NTL, and JPC (HL149303 and HL163857), JA (AI156921), JPC (HL148338 and HL157790), and NTL (HL134740, HL157790). Acknowledgments Publisher Copyright: 2024 Chau, Dominic, Davis, Kotla, Berrios, Fahim, Arunesh, Li, Zhao, Chen, Davis, Nguyen, Wang, Evans, Wang, Cooke, Abe, Huston and Le.

PY - 2023

Y1 - 2023

N2 - BACKGROUND: Traf2 and Nck-interacting kinase (TNIK) is known for its regulatory role in various processes within cancer cells. However, its role within endothelial cells (ECs) has remained relatively unexplored.METHODS: Leveraging RNA-seq data and Ingenuity Pathway Analysis (IPA), we probed the potential impact of TNIK depletion on ECs.RESULTS: Examination of RNA-seq data uncovered more than 450 Differentially Expressed Genes (DEGs) in TNIK-depleted ECs, displaying a fold change exceeding 2 with a false discovery rate (FDR) below 0.05. IPA analysis unveiled that TNIK depletion leads to the inhibition of the interferon (IFN) pathway [-log ( p-value) >11], downregulation of IFN-related genes, and inhibition of Hypercytokinemia/Hyperchemokinemia [-log ( p-value) >8]. The validation process encompassed qRT-PCR to evaluate mRNA expression of crucial IFN-related genes, immunoblotting to gauge STAT1 and STAT2 protein levels, and ELISA for the quantification of IFN and cytokine secretion in siTNIK-depleted ECs. These assessments consistently revealed substantial reductions upon TNIK depletion. When transducing HUVECs with replication incompetent E1-E4 deleted adenovirus expressing green fluorescent protein (Ad-GFP), it was demonstrated that TNIK depletion did not affect the uptake of Ad-GFP. Nonetheless, TNIK depletion induced cytopathic effects (CPE) in ECs transduced with wild-type human adenovirus serotype 5 (Ad-WT). SUMMARY: Our findings suggest that TNIK plays a crucial role in regulating the EC response to virus infections through modulation of the IFN pathway.

AB - BACKGROUND: Traf2 and Nck-interacting kinase (TNIK) is known for its regulatory role in various processes within cancer cells. However, its role within endothelial cells (ECs) has remained relatively unexplored.METHODS: Leveraging RNA-seq data and Ingenuity Pathway Analysis (IPA), we probed the potential impact of TNIK depletion on ECs.RESULTS: Examination of RNA-seq data uncovered more than 450 Differentially Expressed Genes (DEGs) in TNIK-depleted ECs, displaying a fold change exceeding 2 with a false discovery rate (FDR) below 0.05. IPA analysis unveiled that TNIK depletion leads to the inhibition of the interferon (IFN) pathway [-log ( p-value) >11], downregulation of IFN-related genes, and inhibition of Hypercytokinemia/Hyperchemokinemia [-log ( p-value) >8]. The validation process encompassed qRT-PCR to evaluate mRNA expression of crucial IFN-related genes, immunoblotting to gauge STAT1 and STAT2 protein levels, and ELISA for the quantification of IFN and cytokine secretion in siTNIK-depleted ECs. These assessments consistently revealed substantial reductions upon TNIK depletion. When transducing HUVECs with replication incompetent E1-E4 deleted adenovirus expressing green fluorescent protein (Ad-GFP), it was demonstrated that TNIK depletion did not affect the uptake of Ad-GFP. Nonetheless, TNIK depletion induced cytopathic effects (CPE) in ECs transduced with wild-type human adenovirus serotype 5 (Ad-WT). SUMMARY: Our findings suggest that TNIK plays a crucial role in regulating the EC response to virus infections through modulation of the IFN pathway.

KW - interferons

KW - RNA-Seq

KW - STATs

KW - TNIK

KW - virus infection

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U2 - 10.3389/fcvm.2023.1213428

DO - 10.3389/fcvm.2023.1213428

M3 - Article

C2 - 38264262

SN - 2297-055X

VL - 10

SP - 1213428

JO - Frontiers in cardiovascular medicine

JF - Frontiers in cardiovascular medicine

M1 - 1213428

ER -

TNIK regulation of interferon signaling and endothelial cell response to virus infection

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