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

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 and Massimo D’Agostino ()
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Fulvia Vitale: University of Naples Federico II
Gianluca Scerra: University of Naples Federico II
Laura Marrone: University of Naples Federico II
Anna Di Micco: University of Naples Federico II
Magda Cannata Serio: PSL Research University
Amarawan Intasiri: University of Nevada
Giuseppina Amodio: University of Salerno
Vittorio Cirillo: University of Salerno
Paolo Remondelli: University of Salerno
Antonietta Luongo: Via F. Palasciano
Raffaella Bonavita: University of Naples Federico II
Maria Gabriella Caporaso: University of Naples Federico II
Franck Perez: PSL Research University
Maurizio Renna: University of Naples Federico II
Thomas W. Bell: University of Nevada
Simona Romano: University of Naples Federico II
Massimo D’Agostino: University of Naples Federico II

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-62439-w

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