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<p>Severe viral infections can cause cell death as a protective mechanism to eliminate defective cells and limit further viral propagation. However, the precise mechanism underlying the decision between cell survival and death remains unclear. Here, we demonstrate that Engulfment and Cell Motility 1 (ELMO1), an intracellular protein that facilitates cytoskeleton rearrangement through activation of Rac family small GTPase 1 (RAC1), is involved in the Toll-like receptor 3 (TLR3)-induced apoptosis in human umbilical vein endothelial cells. RNA sequencing of cells treated with ELMO1-targeting siRNA (siELMO1) revealed that knockdown of ELMO1 increased the transcripts of extracellular matrix genes including <i>COL5A1</i> and decreased the expression of cell cycle and DNA replication-related genes such as <i>CCND1</i> and <i>CDK1</i>. These siELMO1 treated cells also showed G1/S cell cycle arrest. When stimulated with polyinosinic-polycytidylic acid (poly(I:C)), a TLR3 agonist, inflammatory cytokines and chemokines such as <i>CXCL8</i> and <i>IL6</i> robustly increased in Mock-treated cells, while siNT (non-targeting) cells underwent massive cell death and showed reduced inflammatory responses, reflecting apoptosis-inducing effects of sequential TLR3 activation by siRNA and poly(I:C). Strikingly, siELMO1 cells were resistant to the cell death, and restored inflammatory cytokine responses to the same level as Mock-treated cells. Mechanistically, apoptosis in siNT increased through the activation of caspase-8, whereas downregulation of ELMO1 inhibited the cleavage of caspase-8. These results indicate that ELMO1 is involved in the regulation between survival or death in endothelial cells through the regulation of caspase-8 activity downstream of TLR3, suggesting the importance of the ELMO1 in cell proliferation as well as susceptibility to poly(I:C)-induced apoptosis.</p>

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Downregulation of Engulfment and cell motility 1 (Elmo1) induces quiescence and resistance to poly(I:C)-induced apoptosis in endothelial cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月20日

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  • Yukako Kayashima,
  • Anshulika A. Deshmukh,
  • Yuki Kiyokawa,
  • Niroshani M. W. Wariyapperuma Appuhamillage,
  • Jiayi Zhou,
  • Mohamed-Yahia S. Monawar,
  • Melanie Nassar-Guifarro,
  • Feng Li,
  • Nobuyo Maeda

摘要

Severe viral infections can cause cell death as a protective mechanism to eliminate defective cells and limit further viral propagation. However, the precise mechanism underlying the decision between cell survival and death remains unclear. Here, we demonstrate that Engulfment and Cell Motility 1 (ELMO1), an intracellular protein that facilitates cytoskeleton rearrangement through activation of Rac family small GTPase 1 (RAC1), is involved in the Toll-like receptor 3 (TLR3)-induced apoptosis in human umbilical vein endothelial cells. RNA sequencing of cells treated with ELMO1-targeting siRNA (siELMO1) revealed that knockdown of ELMO1 increased the transcripts of extracellular matrix genes including COL5A1 and decreased the expression of cell cycle and DNA replication-related genes such as CCND1 and CDK1. These siELMO1 treated cells also showed G1/S cell cycle arrest. When stimulated with polyinosinic-polycytidylic acid (poly(I:C)), a TLR3 agonist, inflammatory cytokines and chemokines such as CXCL8 and IL6 robustly increased in Mock-treated cells, while siNT (non-targeting) cells underwent massive cell death and showed reduced inflammatory responses, reflecting apoptosis-inducing effects of sequential TLR3 activation by siRNA and poly(I:C). Strikingly, siELMO1 cells were resistant to the cell death, and restored inflammatory cytokine responses to the same level as Mock-treated cells. Mechanistically, apoptosis in siNT increased through the activation of caspase-8, whereas downregulation of ELMO1 inhibited the cleavage of caspase-8. These results indicate that ELMO1 is involved in the regulation between survival or death in endothelial cells through the regulation of caspase-8 activity downstream of TLR3, suggesting the importance of the ELMO1 in cell proliferation as well as susceptibility to poly(I:C)-induced apoptosis.