Thrombospondin‐1 Regulates Trophoblast Necroptosis via NEDD4‐Mediated Ubiquitination of TAK1 in Preeclampsia

Author:

Hu Haoyue12ORCID,Ma Jing12,Peng You12,Feng Rixuan3,Luo Chenling3,Zhang Minyi4,Tao Zixin5,Chen Lu6,Zhang Tao6,Chen Wenqian12,Yin Qian1,Zhai Jinguo3,Chen Jun1,Yin Ailan1,Wang Chi Chiu6,Zhong Mei1ORCID

Affiliation:

1. Department of Obstetrics and Gynecology Nanfang Hospital Southern Medical University Guangzhou Guangdong 510515 China

2. Guangzhou Key Laboratory of Forensic Multi‐Omics for Precision Identification School of Forensic Medicine Southern Medical University Guangzhou Guangdong 510515 China

3. School of Nursing Southern Medical University Guangzhou Guangdong 510515 China

4. Department of Epidemiology School of Public Health Southern Medical University Guangzhou Guangdong 510515 China

5. Department of Obstetrics and Gynecology Guangzhou First People's Hospital School of Medicine South China University of Technology Guangzhou Guangdong 510180 China

6. Department of Obstetrics and Gynaecology; Li Ka Shing Institute of Health Sciences; School of Biomedical Sciences; Chinese University of Hong Kong‐Sichuan University Joint Laboratory in Reproductive Medicine; The Chinese University of Hong Kong Hong Kong SAR NT China

Abstract

AbstractPreeclampsia (PE) is considered as a disease of placental origin. However, the specific mechanism of placental abnormalities remains elusive. This study identified thrombospondin‐1 (THBS1) is downregulated in preeclamptic placentae and negatively correlated with blood pressure. Functional studies show that THBS1 knockdown inhibits proliferation, migration, and invasion and increases the cycle arrest and apoptosis rate of HTR8/SVneo cells. Importantly, THBS1 silencing induces necroptosis in HTR8/SVneo cells, accompanied by the release of damage‐associated molecular patterns (DAMPs). Necroptosis inhibitors necrostatin‐1 and GSK′872 restore the trophoblast survival while pan‐caspase inhibitor Z‐VAD‐FMK has no effect. Mechanistically, the results show that THBS1 interacts with transforming growth factor B‐activated kinase 1 (TAK1), which is a central modulator of necroptosis quiescence and affects its stability. Moreover, THBS1 silencing up‐regulates the expression of neuronal precursor cell‐expressed developmentally down‐regulated 4 (NEDD4), which acts as an E3 ligase of TAK1 and catalyzes K48‐linked ubiquitination of TAK1 in HTR8/SVneo cells. Besides, THBS1 attenuates PE phenotypes and improves the placental necroptosis in vivo. Taken together, the down‐regulation of THBS1 destabilizes TAK1 by activating NEDD4‐mediated, K48‐linked TAK1 ubiquitination and promotes necroptosis and DAMPs release in trophoblast cells, thus participating in the pathogenesis of PE.

Funder

China Postdoctoral Science Foundation

Nanfang Hospital

National Natural Science Foundation of China

Publisher

Wiley

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