Abstract
SummaryB 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.
Highlights
Chaperone molecules play a crucial role in cellular homeostasis, stabilizing labile proteins during periods of cellular stress
In agreement with a publication studying the role of Aryl hydrocarbon receptor (AHR) in B cells (Villa et al, 2017), following SRBC immunization, we found no differences in Germinal centers (GCs) B cells, B cell lymphoma-6 (BCL6) expression, or antibody production between Ahrfl/fl;Rag1Cre/+ mice and littermate control mice (Figures S4A–S4D)
Using the functionally relevant diffuse large B cell lymphoma (DLBCL) cell line OCI-LY7, we found that Aryl hydrocarbon receptor interacting protein (AIP) could bind to UCHL1 (Figure 5C) and that UCHL1 could bind to BCL6 (Figure 5D), indicating that UCHL1 could be responsible for maintaining BCL6 expression
Summary
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. 2019, Cell Reports 27, 1461–1471 April 30, 2019 a 2019 The Authors.
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