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  3. Thrombospondin-1 Regulates Trophoblast Necroptosis via NEDD4-Mediated Ubiquitination of TAK1 in Preeclampsia

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

  • Adv Sci (Weinh). 2024 Apr 3:e2309002. doi: 10.1002/advs.202309002.
Haoyue Hu 1 2,  Jing Ma 1 2,  You Peng 1 2,  Rixuan Feng 3,  Chenling Luo 3,  Minyi Zhang 4,  Zixin Tao 5,  Lu Chen 6,  Tao Zhang 6,  Wenqian Chen 1 2,  Qian Yin 1,  Jinguo Zhai 3,  Jun Chen 1,  Ailan Yin 1,  Chi Chiu Wang 6,  Mei Zhong 1
Affiliations

Affiliations

  • 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.
PMID: 38569496 DOI: 10.1002/advs.202309002
Abstract

Preeclampsia (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.

Keywords

necroptosis; preeclampsia; thrombospondin‐1; trophoblast; ubiquitination.

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