title: GALNT6 Stabilizes GRP78 Protein by O-glycosylation and Enhances its Activity to Suppress Apoptosis Under Stress Condition.
abstract: We previously reported that overexpression of an O-type glycosyltransferase, GALNT6 (polypeptide N-acetylgalactosaminyltransferase 6) played critical roles in mammary carcinogenesis. To further investigate the biological function of GALNT6, we screened a substrate protein(s) of GALNT6 using a VVA (Vicia villosa agglutinin) lectin (specific to GalNAc-Ser/Thr) pull-down method followed by mass spectrometry analysis. Here we report GRP78 (glucose-regulated protein 78, also known as HSPA5, heat shock 70 kDa protein 5), which is highly expressed in cancer cells and indicated to play important roles in various cellular processes including ER (endoplasmic reticulum) stress and autophagy, as a novel substrate of GALNT6. We found that GALNT6-induced O-glycosylation is critical for the stability of GRP78, its subcellular localization in ER, and its anti-apoptotic function. Furthermore, we demonstrated that overexpression of GRP78 could be important for Golgi-to-ER relocation of GALNT6. Collectively, our study revealed biological significances of O-glycosylation of GRP78 protein, which might play significant roles in the survival of cancer cells, and thus provided a new insight in cancer cell death and useful information for development of anti-cancer treatment targeting the GALNT6-GRP78 pathway.
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Jiaying
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Suyoun
authors.initials: S
authors.lastname: Chung
authors.affiliation: Cancer Proteomics Group, Genome Center, Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Ueda
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuda
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL 60637, USA; Department of Surgery, The University of Chicago, Chicago, IL 60637, USA. Electronic address: ynakamura@bsd.uchicago.edu.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Jae-Hyun
authors.initials: JH
authors.lastname: Park
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D003593:Cytoplasm / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D015870:Gene Expression; D055786:Gene Knockout Techniques; D006031:Glycosylation; D006056:Golgi Apparatus / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D055550:Protein Stability; D021381:Protein Transport; D034622:RNA Interference; D013312:Stress, Physiological; D013379:Substrate Specificity; D000097763:Polypeptide N-acetylgalactosaminyltransferase
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D017350:N-Acetylgalactosaminyltransferases; D000097763:Polypeptide N-acetylgalactosaminyltransferase; C000717247:HSPA5 protein, human