Molecular Stressors Engender Protein Connectivity Dysfunction through Aberrant N-Glycosylation of a Chaperone

• Published in: Cell reports (Cambridge) 2020-06, Vol.31 (13), p.107840-107840, Article 107840
• Main Authors: Yan, Pengrong, Patel, Hardik J., Sharma, Sahil, Corben, Adriana, Wang, Tai, Panchal, Palak, Yang, Chenghua, Sun, Weilin, Araujo, Thais L., Rodina, Anna, Joshi, Suhasini, Robzyk, Kenneth, Gandu, Srinivasa, White, Julie R., de Stanchina, Elisa, Modi, Shanu, Janjigian, Yelena Y., Hill, Elizabeth G., Liu, Bei, Erdjument-Bromage, Hediye, Neubert, Thomas A., Que, Nanette L.S., Li, Zihai, Gewirth, Daniel T., Taldone, Tony, Chiosis, Gabriela
• Format: Article
• Language: English
• Subjects: aberrant N-glycosylation; aberrant protein-protein interaction; Animals; Cell Line, Tumor; cellular stress; chaperome-mediated protein connectivity dysfunction; Cytosol - metabolism; epichaperome; Glycosylation; GRP94; HSP70 Heat-Shock Proteins - chemistry; HSP70 Heat-Shock Proteins - metabolism; Humans; Membrane Proteins - chemistry; Membrane Proteins - metabolism; Mice, Inbred NOD; Molecular Chaperones - metabolism; Molecular Weight; Neoplasms - metabolism; Oncogenes; Polysaccharides - metabolism; Protein Conformation; protein mis-assembly; stable protein assembly; stress-mediated molecular dysfunction; targeted protein degradation-based therapeutics
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.107840

Stresses associated with disease may pathologically remodel the proteome by both increasing interaction strength and altering interaction partners, resulting in proteome-wide connectivity dysfunctions. Chaperones play an important role in these alterations, but how these changes are executed remains largely unknown. Our study unveils a specific N-glycosylation pattern used by a chaperone, Glucose-regulated protein 94 (GRP94), to alter its conformational fitness and stabilize a state most permissive for stable interactions with proteins at the plasma membrane. This “protein assembly mutation’ remodels protein networks and properties of the cell. We show in cells, human specimens, and mouse xenografts that proteome connectivity is restorable by inhibition of the N-glycosylated GRP94 variant. In summary, we provide biochemical evidence for stressor-induced chaperone-mediated protein mis-assemblies and demonstrate how these alterations are actionable in disease. [Display omitted] •N-glycosylation transforms a chaperone, GRP94, from a folder into a scaffolding protein•These changes are pathologic in nature as they remodel proteome-wide connectivity•The N-glycosylated GRP94 variant is a small and distinct fraction of the GRP94 pool•Proteome dysfunctions mediated by the N-glycosylated GRP94 variant are actionable Yan et al. show how N-glycosylation transforms a chaperone from a folding to a scaffolding protein that remodels protein connectivity, with the end result of proteome-wide dysfunction. This specific modification, exploited by cancer cells for enhanced fitness, is an actionable target in disease.