The conserved NUS-1/DHDDS-1 complex links N-glycosylation to lipid and lysosomal homeostasis in C. elegans

N-glycosylation is essential for proteome integrity, yet the systemic roles of the cis-prenyltransferase (cis-PT) complex remain poorly defined. Using Caenorhabditis elegans, we demonstrate that this complex is a dual regulator of global lipid and lysosomal homeostasis. Mechanistically, NUS-1 physically associates with the core oligosaccharyltransferase (OST) complex to coordinate N-glycan transfer. Loss of NUS-1/DHDDS-1 triggers endoplasmic reticulum stress, lysosomal collapse, and systemic lipopenia. This lipid defect arises from impaired N-glycosylation of the SREBP cleavage-activating protein (SCAP). cis-PT deficiency causes unglycosylated SCAP to undergo massive degradation and absolute physical entrapment within the ER, preventing SREBP nuclear translocation and downstream lipid synthesis. Furthermore, pathogenic mutations cause dysfunction through distinct molecular mechanisms: pocket integrity disruption or catalytic impairment. These findings uncover an essential crosstalk between protein glycosylation and global lipid metabolism, providing a mechanistic framework for understanding the systemic pathophysiology of congenital disorders of glycosylation (CDG).