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Elucidation of the AGR2 interactome in esophageal adenocarcinoma cells identifies a redox sensitive chaperone hub for the quality control of MUC-5AC

Worfolk, JC; Bell, S; Simpson, LD; Carne, NA; Francis, SL; Engelbertsen, V; Brown, AP; Walker, J; Viswanath, YK; Benham, AM

Elucidation of the AGR2 interactome in esophageal adenocarcinoma cells identifies a redox sensitive chaperone hub for the quality control of MUC-5AC Thumbnail


Authors

JC Worfolk

LD Simpson

NA Carne

SL Francis

V Engelbertsen

AP Brown

J Walker

YK Viswanath



Abstract

Aims: AGR2 is a tissue-restricted member of the protein disulfide isomerase family that has attracted interest because it is highly expressed in a number of cancers, including gastroesophageal adenocarcinoma. The behavior of AGR2 was analyzed under oxidizing conditions, and an alkylation trapping and immunoprecipitation approach were developed to identify novel AGR2 interacting proteins. Results: The data show that AGR2 is induced in esophageal adenocarcinoma, where it participates in redox-responsive, disulfide-dependent complexes. AGR2 preferentially engages with MUC-5 as a primary client and is coexpressed with the acidic mucin in Barrett's esophagus and esophageal adenocarcinoma tissue. Innovation: New partner chaperones for AGR2 have been identified, including peroxiredoxin IV, ERp44, P5, ERp29, and Ero1α. AGR2 interacts with unexpected metabolic enzymes, including aldehyde dehydrogenase (ALDH)3A1, and engages in an alkylation-sensitive association with the autophagy receptor SQSTM1, suggesting a potential mechanism for the postendoplasmic reticulum targeting of AGR2 to mucin granules. Disulfide-driven AGR2 complex formation provides a framework for a limited number of client proteins to interact, rather than for the recruitment of multiple novel clients. Conclusion: The extended AGR2 interactome will facilitate the development of therapeutics to target AGR2/mucin pathways in esophageal cancer and other conditions, including chronic obstructive pulmonary disease.

Citation

Worfolk, J., Bell, S., Simpson, L., Carne, N., Francis, S., Engelbertsen, V., …Benham, A. (2019). Elucidation of the AGR2 interactome in esophageal adenocarcinoma cells identifies a redox sensitive chaperone hub for the quality control of MUC-5AC. Antioxidants and Redox Signaling, 31(15), 1117-1132. https://doi.org/10.1089/ars.2018.7647

Journal Article Type Article
Acceptance Date Aug 22, 2019
Online Publication Date Oct 16, 2019
Publication Date Nov 30, 2019
Deposit Date Aug 22, 2019
Publicly Available Date Oct 16, 2020
Journal Antioxidants and Redox Signaling
Print ISSN 1523-0864
Electronic ISSN 1557-7716
Publisher Mary Ann Liebert
Peer Reviewed Peer Reviewed
Volume 31
Issue 15
Pages 1117-1132
DOI https://doi.org/10.1089/ars.2018.7647
Public URL https://durham-repository.worktribe.com/output/1324281

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