Aryl Hydrocarbon Receptor Interacting Protein Maintains Germinal Center B Cells through Suppression of BCL6 Degradation
Dijue Sun,
Urszula Stopka-Farooqui,
Sayka Barry,
Ezra Aksoy,
Gregory Parsonage,
Anna Vossenkämper,
Melania Capasso,
Xinyu Wan,
Sherine Norris,
Jennifer L. Marshall,
Andrew Clear,
John Gribben,
Thomas T. MacDonald,
Christopher D. Buckley,
Márta Korbonits,
Oliver Haworth
Affiliations
Dijue Sun
Center of Biochemical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
Urszula Stopka-Farooqui
Center of Biochemical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
Sayka Barry
Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
Ezra Aksoy
Center of Biochemical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
Gregory Parsonage
Experimental Medicine & Rheumatology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
Anna Vossenkämper
Center for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
Melania Capasso
Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
Xinyu Wan
Center of Biochemical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
Sherine Norris
Center of Biochemical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
Jennifer L. Marshall
Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK
Andrew Clear
Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
John Gribben
Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
Thomas T. MacDonald
Center for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
Christopher D. Buckley
Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK
Márta Korbonits
Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
Oliver Haworth
Center of Biochemical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; Department of Biological Sciences, Westminster University, London W1W 6UW, UK; Corresponding author
Summary: B cell lymphoma-6 (BCL6) is highly expressed in germinal center B cells, but how its expression is maintained is still not completely clear. Aryl hydrocarbon receptor interacting protein (AIP) is a co-chaperone of heat shock protein 90. Deletion of Aip in B cells decreased BCL6 expression, reducing germinal center B cells and diminishing adaptive immune responses. AIP was required for optimal AKT signaling in response to B cell receptor stimulation, and AIP protected BCL6 from ubiquitin-mediated proteasomal degradation by the E3-ubiquitin ligase FBXO11 by binding to the deubiquitinase UCHL1, thus helping to maintain the expression of BCL6. AIP was highly expressed in primary diffuse large B cell lymphomas compared to healthy tissue and other tumors. Our findings describe AIP as a positive regulator of BCL6 expression with implications for the pathobiology of diffuse large B cell lymphoma. : BCL6 overexpression contributes to the pathobiology of diffuse large B cell lymphoma (DLBCL). Sun et al. find that the co-chaperone aryl hydrocarbon receptor interacting protein (AIP), whose high expression is associated with reduced survival of DLBCL patients, helps maintain BCL6 expression by facilitating the removal of ubiquitin from BCL6. Keywords: AIP, BCL6, FBXO11, UCHL1, ubiquitination, lymphoma
