Aryl Hydrocarbon Receptor Interacting Protein Maintains Germinal Center B Cells through Suppression of BCL6 Degradation

• Published in: Cell reports (Cambridge) Vol. 27; no. 5; pp. 1461 - 1471.e4
• Main Authors: Sun, Dijue, Stopka-Farooqui, Urszula, Barry, Sayka, Aksoy, Ezra, Parsonage, Gregory, Vossenkämper, Anna, Capasso, Melania, Wan, Xinyu, Norris, Sherine, Marshall, Jennifer L., Clear, Andrew, Gribben, John, MacDonald, Thomas T., Buckley, Christopher D., Korbonits, Márta, Haworth, Oliver
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30-04-2019; Cell Press; Elsevier
• Subjects: Adult; Aged; Aged, 80 and over; AIP; Animals; B-Lymphocytes - immunology; BCL6; F-Box Proteins - metabolism; FBXO11; Female; Germinal Center - cytology; Germinal Center - immunology; HEK293 Cells; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; lymphoma; Lymphoma, Large B-Cell, Diffuse - immunology; Male; Mice; Middle Aged; Proteasome Endopeptidase Complex - metabolism; Protein Binding; Protein-Arginine N-Methyltransferases - metabolism; Proteolysis; Proto-Oncogene Proteins c-bcl-6 - metabolism; Ubiquitin Thiolesterase - metabolism; Ubiquitination; UCHL1; AIP; UCHL1; BCL6; ubiquitination; FBXO11; lymphoma
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.04.014

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.
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•AIP supports BCL6 expression in germinal center and DLBCL cells•AIP inhibits BCL6 degradation by regulating the deubiquitinase UCHL1•AIP is highly expressed in DLBCL and is associated with decreased survival in DLBCL
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.