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Theranostics 2020; 10(25):11479-11496. doi:10.7150/thno.49870 This issue Cite

Research Paper

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

Bang-Chuan Hu1, Guo-Hua Wu2, Zi-Qiang Shao1, Yang Zheng1, Jin-Quan Liu1, Run Zhang1, Jun Hong1, Xiang-Hong Yang1, Ren-Hua Sun1, Shi-Jing Mo1✉

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.

✉ Corresponding author: Shi-Jing Mo, MD, PhD, Department of Intensive Care Unit, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China. E-mail: moshijingedu.cn; ORCID: https:// More

Citation:
Hu BC, Wu GH, Shao ZQ, Zheng Y, Liu JQ, Zhang R, Hong J, Yang XH, Sun RH, Mo SJ. Redox DAPK1 destabilizes Pellino1 to govern inflammation-coupling tubular damage during septic AKI. Theranostics 2020; 10(25):11479-11496. doi:10.7150/thno.49870. https://www.thno.org/v10p11479.htm
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Abstract

Graphic 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: Septic acute kidney injury, Tubular damage, DAPK1, Phosphorylation, Pellino1, Turnover

Citation styles

APA
Hu, B.C., Wu, G.H., Shao, Z.Q., Zheng, Y., Liu, J.Q., Zhang, R., Hong, J., Yang, X.H., Sun, R.H., Mo, S.J. (2020). Redox DAPK1 destabilizes Pellino1 to govern inflammation-coupling tubular damage during septic AKI. Theranostics, 10(25), 11479-11496. https://doi.org/10.7150/thno.49870.

ACS
Hu, B.C.; Wu, G.H.; Shao, Z.Q.; Zheng, Y.; Liu, J.Q.; Zhang, R.; Hong, J.; Yang, X.H.; Sun, R.H.; Mo, S.J. Redox DAPK1 destabilizes Pellino1 to govern inflammation-coupling tubular damage during septic AKI. Theranostics 2020, 10 (25), 11479-11496. DOI: 10.7150/thno.49870.

NLM
Hu BC, Wu GH, Shao ZQ, Zheng Y, Liu JQ, Zhang R, Hong J, Yang XH, Sun RH, Mo SJ. Redox DAPK1 destabilizes Pellino1 to govern inflammation-coupling tubular damage during septic AKI. Theranostics 2020; 10(25):11479-11496. doi:10.7150/thno.49870. https://www.thno.org/v10p11479.htm

CSE
Hu BC, Wu GH, Shao ZQ, Zheng Y, Liu JQ, Zhang R, Hong J, Yang XH, Sun RH, Mo SJ. 2020. Redox DAPK1 destabilizes Pellino1 to govern inflammation-coupling tubular damage during septic AKI. Theranostics. 10(25):11479-11496.

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