A delayed translocation into the endoplasmic reticulum controls the post-translational modifications of PD-L1
Abstract
N-terminal signal peptides (SPs) are traditionally considered as drivers of co-translational translocation of newly synthesised proteins into the endoplasmic reticulum (ER). However, growing evidences suggest that proteins with SPs can also undergo post-translational insertion into the ER membrane after synthesis is complete. Recently, an intermediate third mechanism has been uncovered where proteins with marginally hydrophobic or suboptimal SPs are translocated following an initial delay after translation initiation. Here, we show that this “delayed translocation” allows a temporary exposure of the nascent chain to the cytosolic environment, enabling exoplasmic domain modifications by cytosolic enzymes. We report that programmed death ligand-1 (PD-L1) follows this pathway, featuring a suboptimal SP that exposes its extracellular domain to the cytosol, enabling AMPK-dependent regulation of PD-L1 function. Importantly, optimising the SP of PD-L1 eliminates the cytosolic exposure, disrupting PD-L1’s trafficking and maturation, highlighting the physiological importance of the delayed translocation mechanism.
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BibTeX
@article{serio2026delayed,
title = {{A delayed translocation into the endoplasmic reticulum controls the post-translational modifications of PD-L1}},
author = {Magda Cannata Serio and Fulvia Vitale and Gianluca Scerra and Raffaella Bonavita and Patrick Poullet and Maria Gabriella Caporaso and Laura Marrone and Simona Romano and Maurizio Renna and Franck Perez and Massimo D’agostino},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-71760-x},
url = {https://hal.science/hal-05780951v1},
note = {CC BY-SA 4.0},
}
RIS
TY - JOUR
TI - A delayed translocation into the endoplasmic reticulum controls the post-translational modifications of PD-L1
AU - Magda Cannata Serio
AU - Fulvia Vitale
AU - Gianluca Scerra
AU - Raffaella Bonavita
AU - Patrick Poullet
AU - Maria Gabriella Caporaso
AU - Laura Marrone
AU - Simona Romano
AU - Maurizio Renna
AU - Franck Perez
AU - Massimo D’agostino
PY - 2026
DA - 2026/10/06
JO - Nature Communications
DO - 10.1038/s41467-026-71760-x
UR - https://hal.science/hal-05780951v1
AB - N-terminal signal peptides (SPs) are traditionally considered as drivers of co-translational translocation of newly synthesised proteins into the endoplasmic reticulum (ER). However, growing evidences suggest that proteins with SPs can also undergo post-translational insertion into the ER membrane after synthesis is complete. Recently, an intermediate third mechanism has been uncovered where proteins with marginally hydrophobic or suboptimal SPs are translocated following an initial delay after translation initiation. Here, we show that this “delayed translocation” allows a temporary exposure of the nascent chain to the cytosolic environment, enabling exoplasmic domain modifications by cytosolic enzymes. We report that programmed death ligand-1 (PD-L1) follows this pathway, featuring a suboptimal SP that exposes its extracellular domain to the cytosol, enabling AMPK-dependent regulation of PD-L1 function. Importantly, optimising the SP of PD-L1 eliminates the cytosolic exposure, disrupting PD-L1’s trafficking and maturation, highlighting the physiological importance of the delayed translocation mechanism.
SN - 2041-1723
SN - 2041-1723
ER -