{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ALG3 encodes an endoplasmic reticulum α‐1,3‐mannosyltransferase that plays a critical role in the synthesis of the lipid‐linked oligosaccharide precursor required for N‐glycosylation. In several cancer types, increased ALG3 expression is associated with aggressive tumor behavior. For instance, studies in breast cancer have shown that ALG3 overexpression drives radioresistance and promotes cancer stemness through enhanced glycosylation of key receptors such as TGF‐β receptor II"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "and via transcriptional mechanisms involving HSF2."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Similarly, in non‐small cell lung cancer and oral squamous cell carcinoma, high ALG3 levels correlate with advanced disease stage, lymph node metastasis, and accelerated cell cycle progression via the activation of CDK–Cyclin pathways."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Data from head and neck as well as bladder cancer further support a pro‐tumorigenic role for ALG3, with its expression being linked to poor clinical outcomes and decreased CD8⁺ T‐cell infiltration in lung adenocarcinoma."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In contrast, loss‐of‐function mutations in ALG3 result in a subset of congenital disorders of glycosylation (ALG3‐CDG) that manifest as multisystem developmental defects—including severe neurological impairment, skeletal dysplasia, ocular abnormalities, and endocrine dysfunction—with patients often exhibiting a type I serum transferrin pattern. Clinical case series and molecular studies have expanded the spectrum of ALG3‐CDG, highlighting novel pathogenic variants and underscoring the essential nature of proper ALG3 function for normal glycoprotein processing."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "11"}]}, {"type": "t", "text": " In addition, defects in ALG3 activity have been linked to impaired secretion and function of insulin‐like growth factor 1 (IGF‐1) components in patient fibroblasts, thereby compromising growth factor signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond human pathophysiology, ALG3 is also essential in other biological contexts. In the rice blast fungus Magnaporthe oryzae, ALG3 is required for the proper N‐glycosylation, secretion, and localization of virulence factors that maintain cell wall integrity and enable host colonization."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " In biotechnological applications, targeted disruption of ALG3 in yeast species is exploited to modulate glycosylation patterns, thereby enabling the production of humanized glycoproteins with reduced hypermannosylation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": " Moreover, genome‐wide screens have revealed that loss of ALG3 can impair the proper folding of viral glycoproteins, resulting in decreased susceptibility to dengue virus infection"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "; studies in yeast also indicate that alterations in ALG3 activity can affect endoplasmic reticulum–associated degradation of glycoproteins."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": " Finally, protein–protein interaction analyses have identified multiple binding partners of the human ALG3 ortholog, suggesting that ALG3 participates in diverse molecular networks that may influence cancer, viral infections, and congenital glycosylation disorders."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies demonstrate that ALG3 functions in a context‐dependent manner: its overexpression contributes to oncogenic processes and tumor progression, whereas its deficiency leads to severe congenital disorders of glycosylation. This duality highlights the importance of precise regulation of N‐glycosylation in both health and disease.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Xiaoqing Sun, Zhenyu He, Ling Guo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ALG3 contributes to stemness and radioresistance through regulating glycosylation of TGF-β receptor II in breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Clin Cancer Res (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s13046-021-01932-8"}], "href": "https://doi.org/10.1186/s13046-021-01932-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33931075"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33931075"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Yongde Yang, Yanlin Zhou, Xin Xiong, et al. 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