1. Academic Validation
  2. Redox DAPK1 destabilizes Pellino1 to govern inflammation-coupling tubular damage during septic AKI

Redox DAPK1 destabilizes Pellino1 to govern inflammation-coupling tubular damage during septic AKI

  • Theranostics. 2020 Sep 15;10(25):11479-11496. doi: 10.7150/thno.49870.
Bang-Chuan Hu 1 Guo-Hua Wu 2 Zi-Qiang Shao 1 Yang Zheng 1 Jin-Quan Liu 1 Run Zhang 1 Jun Hong 1 Xiang-Hong Yang 1 Ren-Hua Sun 1 Shi-Jing Mo 1
Affiliations

Affiliations

  • 1 Department of Intensive Care Unit, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang, P.R.China.
  • 2 Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310029, Zhejiang, P.R.China.
Abstract

Tubular damage initiated by inflammatory response and ischemic/hypoxic stress is a hallmark of septic acute kidney injury (AKI), albeit the molecular mechanism coupling the two events remains unclear. We investigated the intrinsic nature of tubular damage with respect to inflammatory/hypoxic stress during septic AKI. Methods: The apoptotic response of tubular cells to LPS stimuli was analyzed before and after hypoxia exposure. Cellular ubiquitination, co-immunoprecipitation, GST-pulldown, in vitro protein kinase assay, immunofluorescence and CRISPR technology were adopted to determine the molecular mechanism underlying this process. In vivo characterization was performed in wild-type and DAPK1-/- mice models of cecal ligation and puncture (CLP). Results: We found that the MyD88-dependent inflammatory response couples to tubular damage during LPS stimuli under hypoxia in a Fn14/SCFFbxw7α-dispensable manner via recruitment of Caspase-8 with TRIF-RIP1 signalosome mediated by DAPK1, which directly binds to and phosphorylates Pellino1 at Ser39, leading to Pellino1 poly-ubiquitination and turnover. Either pharmacological deactivation or genetic ablation of DAPK1 makes tubular cells refractory to the LPS-induced damage in the context of hypoxia, while kinase activity of DAPK1 is essential for ruin execution. Targeting DAPK1 effectively protects mice against septic AKI and potentiates the efficacy of a MyD88 homodimerization inhibitor, ST2825. Conclusion: Our findings provide a rationale for the mechanism whereby inflammation intersects with hypoxic tubular damage during septic AKI through a previously unappreciated role of DAPK1-inducible Ser39 phosphorylation in Pellino1 turnover and underscore that combined targeting DAPK1 and MyD88 might be a feasible strategy for septic AKI management.

Keywords

DAPK1; Pellino1; Phosphorylation; Septic acute kidney injury; Tubular damage; Turnover.

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