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IFI16 is essential to linking DNA damage and ferroptosis in acute kidney injury
Zhe Qiao1, Di Zhou1, Tianxing Zhang1
1The Key Laboratory of Infection and Immunity of Shandong Province, Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, China.
Abstract:
Emerging evidence demonstrates the important role of ferroptosis, a novel regulated cell death, in the initiation and progression of acute kidney injury (AKI). However, the activation mechanism of ferroptosis in AKI has not been fully revealed. The pivotal function of interferon inducible protein 16 (IFI16) in DNA damage response (DDR) as DNA sensor and regulator of cell death pathways encouraged us to examine its role in ferroptosis of renal tubular epithelial cells (TECs) in AKI. Here we report that the levels of IFI16 and its mouse ortholog p204 were elevated in the kidney of patients with acute tubular necrosis (ATN) and in TECs of mice with renal ischemia/reperfusion (I/R)-induced AKI (I/R-AKI). Under I/R conditions, tubule-specific p204 deficiency in mice and IFI16 knockout in HK-2 cells significantly ameliorated TEC ferroptosis. Mechanistically, IFI16 binds to poly(ADP-ribose) polymerase 1 (PARP-1) and enhances protein Poly ADP-ribosylation (PARylation), which in turn potentiates the ataxia-telangiectasia mutated (ATM)-p53 signaling contributing to lipid peroxidation and ferrous ion accumulation in TECs. In addition, IFI16-amplified DDR was dependent on its HIN and PYRIN domains. Thus, our findings provide a better understanding of a critical pathogenic axis linking DNA damage to ferroptosis and suggest that targeting IFI16 may be an innovative therapeutic strategy for treating patients with AKI.
Insights
Interferon inducible protein 16 (IFI16) drives ferroptosis in acute kidney injury (AKI) by linking DNA damage to cell death. Targeting IFI16 may offer a new therapeutic strategy for AKI patients.
Area of Science:
- Nephrology
- Cell Biology
- Molecular Medicine
Background:
- Ferroptosis, a regulated cell death, is implicated in acute kidney injury (AKI) pathogenesis.
- The precise mechanisms activating ferroptosis in AKI remain incompletely understood.
- Interferon inducible protein 16 (IFI16) is known for its roles in DNA damage response (DDR) and cell death regulation.
Purpose of the Study:
- To investigate the role of IFI16 in ferroptosis within renal tubular epithelial cells (TECs) during AKI.
- To elucidate the molecular mechanisms by which IFI16 influences ferroptosis in the context of AKI.
Main Methods:
- Quantification of IFI16/p204 levels in human AKI kidneys and mouse models of ischemia/reperfusion (I/R)-induced AKI.
- Assessment of TEC ferroptosis in tubule-specific p204-deficient mice and IFI16 knockout HK-2 cells under I/R conditions.
- Mechanistic studies involving IFI16 binding to PARP-1, protein poly ADP-ribosylation (PARylation), and ATM-p53 signaling.
Main Results:
- IFI16 and its mouse ortholog p204 were upregulated in AKI kidneys and TECs.
- Depletion of p204 or IFI16 significantly reduced TEC ferroptosis in I/R-AKI models.
- IFI16 was found to bind PARP-1, enhancing PARylation and potentiating ATM-p53 signaling, leading to ferroptosis.
Conclusions:
- IFI16 plays a critical role in promoting ferroptosis in TECs during AKI.
- The IFI16-PARP-1-ATM-p53 axis represents a key pathway linking DNA damage to ferroptosis in AKI.
- Targeting IFI16 presents a potential novel therapeutic strategy for AKI treatment.
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