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<p>Inhibition of endothelial cell (EC) death is essential for normal angiogenesis. The E3 ubiquitin ligase HOIP, the catalytic subunit of the linear ubiquitin chain assembly complex (LUBAC), is particularly important for EC survival during embryogenesis. The stability of HOIP is critical for LUBAC function. However, the mechanisms underlying the regulation of HOIP stability are largely unknown. Here, we uncovered a novel role of G protein pathway suppressor 2 (GPS2) in regulating EC survival and embryonic vascularization via control of HOIP stability. EC-specific GPS2 deletion mice (<i>Gps2</i><sup><i>ECKO</i></sup>) are embryonic lethal at embryonic day 16.5 (E16.5) due to defective vascularization. Deficiency of GPS2 in ECs results in aberrant TNFR1-mediated cell death. TNFR1 deletion in <i>Gps2</i><sup><i>ECKO</i></sup> mice restores normal vascularization and rescues embryonic lethality. At the molecular level, GPS2 binds to the NZF domain of HOIP and inhibits K48-linked polyubiquitination of HOIP at K579, K737, and K988 residues. GPS2 prevents HOIP proteasomal degradation and thus maintains LUBAC stability and activity. GPS2 deficiency in ECs leads to HOIP degradation and LUBAC instability, which in turn attenuates TNF-induced NF-κB activation and exacerbates the formation of the cell-death-inducing complex-II, ultimately increasing EC death. Overall, our data demonstrate that GPS2 is required for maintaining vascular integrity during embryogenesis by inhibiting TNFR1-mediated EC death via stabilizing HOIP.</p>

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GPS2 regulates embryonic angiogenesis by enhancing endothelial cell survival through stabilizing HOIP

  • 期刊论文

  • 发表日期：

    2026年1月8日

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  • Ying Lu,
  • Huan-Huan Tian,
  • Wen-Bing Ma,
  • Jin-Jin Lu,
  • Jun Wang,
  • Jun-Jie Bi,
  • Guang-Ming Ren,
  • Xian Liu,
  • Ya-Ting Li,
  • Ting Wang,
  • Shen-Si Xiang,
  • Chang-Yan Li,
  • Miao Yu,
  • Ke Zhao,
  • Jing-Jing Li,
  • Hui-Ying Gao,
  • Hui Chen,
  • Yi-Qun Zhan,
  • Rong-Hua Yin,
  • Xiao-Ming Yang

摘要

Inhibition of endothelial cell (EC) death is essential for normal angiogenesis. The E3 ubiquitin ligase HOIP, the catalytic subunit of the linear ubiquitin chain assembly complex (LUBAC), is particularly important for EC survival during embryogenesis. The stability of HOIP is critical for LUBAC function. However, the mechanisms underlying the regulation of HOIP stability are largely unknown. Here, we uncovered a novel role of G protein pathway suppressor 2 (GPS2) in regulating EC survival and embryonic vascularization via control of HOIP stability. EC-specific GPS2 deletion mice (Gps2ECKO) are embryonic lethal at embryonic day 16.5 (E16.5) due to defective vascularization. Deficiency of GPS2 in ECs results in aberrant TNFR1-mediated cell death. TNFR1 deletion in Gps2ECKO mice restores normal vascularization and rescues embryonic lethality. At the molecular level, GPS2 binds to the NZF domain of HOIP and inhibits K48-linked polyubiquitination of HOIP at K579, K737, and K988 residues. GPS2 prevents HOIP proteasomal degradation and thus maintains LUBAC stability and activity. GPS2 deficiency in ECs leads to HOIP degradation and LUBAC instability, which in turn attenuates TNF-induced NF-κB activation and exacerbates the formation of the cell-death-inducing complex-II, ultimately increasing EC death. Overall, our data demonstrate that GPS2 is required for maintaining vascular integrity during embryogenesis by inhibiting TNFR1-mediated EC death via stabilizing HOIP.