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<p>The perturbation of protein translocation into the secretory pathway using Sec61 translocon inhibitors is a novel and promising strategy for tackling many pathological situations, including cancer and viral infections. However, a highly sensitive and direct screening platform for selecting Sec61 inhibitors is unavailable. Here, we develop a “<i>resuming luminescence upon translocation interference”</i> (RELITE) assay capable of selecting Sec61 inhibitors in a single round of screening. This assay exploits the inactivation of <i>firefly</i> luciferase, once translocated into the endoplasmic reticulum (ER), and the possibility of diverting and “re-lighting” luciferase into the cytosol by a Sec61 inhibitor. Using this method, we select small molecules capable of hampering the protein expression of the PD-L1 immune checkpoint by interfering with its ER translocation and delivering it for degradation. In conclusion, our screening method will greatly facilitate the selection of Sec61 inhibitors for down-modulating the expression of many disease-relevant proteins.</p>

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A light-resuming strategy as a screening method for selecting Sec61 inhibitors down-modulating PD-L1 expression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月6日

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  • Fulvia Vitale,
  • Gianluca Scerra,
  • Laura Marrone,
  • Anna Di Micco,
  • Magda Cannata Serio,
  • Amarawan Intasiri,
  • Giuseppina Amodio,
  • Vittorio Cirillo,
  • Paolo Remondelli,
  • Antonietta Luongo,
  • Raffaella Bonavita,
  • Maria Gabriella Caporaso,
  • Franck Perez,
  • Maurizio Renna,
  • Thomas W. Bell,
  • Simona Romano,
  • Massimo D’Agostino

摘要

The perturbation of protein translocation into the secretory pathway using Sec61 translocon inhibitors is a novel and promising strategy for tackling many pathological situations, including cancer and viral infections. However, a highly sensitive and direct screening platform for selecting Sec61 inhibitors is unavailable. Here, we develop a “resuming luminescence upon translocation interference” (RELITE) assay capable of selecting Sec61 inhibitors in a single round of screening. This assay exploits the inactivation of firefly luciferase, once translocated into the endoplasmic reticulum (ER), and the possibility of diverting and “re-lighting” luciferase into the cytosol by a Sec61 inhibitor. Using this method, we select small molecules capable of hampering the protein expression of the PD-L1 immune checkpoint by interfering with its ER translocation and delivering it for degradation. In conclusion, our screening method will greatly facilitate the selection of Sec61 inhibitors for down-modulating the expression of many disease-relevant proteins.