Language

English

Publication Date

6-29-2026

Journal

Cell Reports

DOI

10.1016/j.celrep.2026.117628

PMID

42378087

Abstract

Trimming of the three glucose residues decorating nascent N-glycoproteins is a critical step for their entry into the endoplasmic reticulum quality control (ERQC) and recognition by ER chaperones. However, the functional relevance of the second glucose (G2) and the regulatory step upstream of its removal by glucosidase II (GCS2) remain poorly understood. Here, we report that TUSC3, a component of the oligosaccharyltransferase (OST) complex, regulates G2 to G1 trimming on N-glycosylated bone morphogenetic protein 4 (BMP4) and its Drosophila homolog Dpp to promote their ERQC entry. Loss- and gain-of-function genetic experiments and biochemical assays in mammalian cells and flies indicate that TUSC3 serves as a dosage-sensitive gatekeeper that influences the decision between proper folding and secretion versus elimination by ER-associated degradation for the BMP4 molecules, thereby tuning BMP signaling. Together, these data reveal an unrecognized role for an OST component in early glycoprotein maturation, relevant to a major developmental signaling pathway.

Keywords

BMP signaling, CP: cell biology, Drosophila, ER-associated degradation, OST complex, TUSC3, deglycosylation, endoplasmic reticulum, glucosidase II, glycosylation, oligosaccharyltransferase complex, quality control

Published Open-Access

yes

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