Alpha-1,3-mannosyltransferase ALG3 (ALG3)

Alpha-1,3-mannosyltransferase ALG3 is an essential enzyme located in the endoplasmic reticulum membrane that participates in the early stages of N-linked glycosylation (UniProt, NIH). It catalyzes the transfer of the first dolichol-phosphate-mannose-derived mannose residue to the lipid-linked oligosaccharide precursor Man5GlcNAc2-PP-Dol (PubMed, Wikipedia). While germline mutations in the ALG3 gene lead to the rare and severe multisystemic disorder Congenital Disorder of Glycosylation type Id (ALG3-CDG), its somatic overexpression is a hallmark of several aggressive cancers, including breast, lung, and bladder carcinomas (NIH, CDG Hub). In these malignancies, ALG3 promotes tumor progression by ensuring the proper glycosylation and stability of key oncogenic proteins such as EGFR, TGFBR2, and CD44, which in turn drives cell proliferation, metastasis, and resistance to chemotherapy and targeted agents (PubMed, ResearchGate). Emerging research identifies ALG3 as a promising therapeutic target, as its inhibition can induce endoplasmic reticulum stress, trigger immunogenic ferroptosis, and synergize with immune checkpoint inhibitors and targeted therapies like cetuximab (NIH, Nature).

Other names

Dol-P-Man:Man(5)GlcNAc(2)-PP-Dol alpha-1,3-mannosyltransferaseAsparagine-linked glycosylation 3 homologCDG1DCDGS4NOT56LNot56CDGS6notAlpha-1,3-mannosyltransferase

Inhibition of ALG3 disrupts the assembly of lipid-linked oligosaccharides, leading to N-glycosylation deficiency and the induction of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). This results in the downregulation of oncogenic signaling pathways (e.g., EGFR, TGF-beta), induction of immunogenic ferroptosis, and sensitization of cancer cells to chemotherapy, targeted therapy, and immunotherapy (PubMed, NIH).