The impact of the cytoplasmic ubiquitin ligase TNFAIP3 gene variation on transcription factor NF-κB activation in acute kidney injury

Date

2023

Authors

Rogers, N.M.
Zammit, N.
Nguyen-Ngo, D.
Souilmi, Y.
Minhas, N.
Meijles, D.N.
Self, E.
Walters, S.N.
Warren, J.
Cultrone, D.

Editors

Advisors

Journal Title

Journal ISSN

Volume Title

Type:

Journal article

Citation

Kidney International, 2023; 103(6):1105-1119

Statement of Responsibility

Natasha M. Rogers, Nathan Zammit, Danny Nguyen-Ngo, Yassine Souilmi, Nikita Minhas, Daniel N. Meijles, Eleanor Self, Stacey N. Walters, Joanna Warren, Daniele Cultrone, Maryam El-Rashid, Jennifer Li, Tatyana Chtanova, Philip J. O, Connell, and Shane T. Grey

Conference Name

DOI

10.1016/j.kint.2023.02.030

Abstract

Nuclear factor kB (NF-kB) activation is a deleterious molecular mechanism that drives acute kidney injury (AKI) and manifests in transplanted kidneys as delayed graft function. The TNFAIP3 gene encodes A20, a cytoplasmic ubiquitin ligase and a master negative regulator of the NF- kB signaling pathway. Common population-specific TNFAIP3 coding variants that reduce A20’s enzyme function and increase NF- kB activation have been linked to heightened protective immunity and autoimmune disease, but have not been investigated in AKI. Here, we functionally identified a series of unique human TNFAIP3 coding variants linked to the autoimmune genome-wide association studies single nucleotide polymorphisms of F127C; namely F127C;R22Q, F127C;G281E, F127C;W448C and F127C;N449K that reduce A20’s anti-inflammatory function in an NF- kB reporter assay. To investigate the impact of TNFAIP3 hypomorphic coding variants in AKI we tested a mouse Tnfaip3 hypomorph in a model of ischemia reperfusion injury (IRI). The mouse Tnfaip3 coding variant I325N increases NF- kB activation without overt inflammatory disease, providing an immune boost as I325N mice exhibit enhanced innate immunity to a bacterial challenge. Surprisingly, despite exhibiting increased intra-kidney NF- kB activation with inflammation in IRI, the kidney of I325N mice was protected. The I325N variant influenced the outcome of IRI by changing the dynamic expression of multiple cytoprotective mechanisms, particularly by increasing NF- kB-dependent anti-apoptotic factors BCL-2, BCL-XL, c-FLIP and A20, altering the active redox state of the kidney with a reduction of superoxide levels and the enzyme super oxide dismutase-1, and enhancing cellular protective mechanisms including increased Foxp3D T cells. Thus, TNFAIP3 gene variants represent a kidney and population-specific molecular factor that can dictate the course of IRI.

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Dissertation Note

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Description

Access Status

Rights

© 2023, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

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Grant ID

http://purl.org/au-research/grants/nhmrc/GNT1138372
 http://purl.org/au-research/grants/nhmrc/GNT1130222
 http://purl.org/au-research/grants/nhmrc/GNT1146493
 http://purl.org/au-research/grants/nhmrc/GNT1189235
 http://purl.org/au-research/grants/nhmrc/GNT1158977
 http://purl.org/au-research/grants/nhmrc/GNT1140691

Published Version

https://doi.org/10.1016/j.kint.2023.02.030

Call number

Persistent link to this record

https://hdl.handle.net/2440/140096