Regulation of the HSH2 adaptor protein turnover via an indirect NF-κB-dependent mechanism is involved in determining the nature of the class switched antibody response. (IRM10P.609)

Abstract

Abstract The Hematopoietic SH2 containing adaptor protein (HSH2) is differentially expressed in mature, peripheral B cell subpopulations, exhibiting low level expression in germinal center (GC) B cells versus high-level expression in B1 and marginal zone B cells. Studies have demonstrated an inverse relationship between its expression and the production of class-switched antibodies due to effects on terminal differentiation. Therefore, delineation of molecular mechanism that controls its expression is critical for understanding the class-switched antibody response. Studies demonstrated that upregulation of HSH2 following TNF family receptor or TLR-mediated signals, as well as its maintenance, requires NF-κB activity. Using both pharmacological and genetic approaches, it was shown that the canonical pathway is critical for maintenance of HSH2 expression. Inhibition of NF-kB selectively results in the rapid loss of HSH2, whereas actinomycin D and cycloheximide treatment do not. Analysis of the canonical pathway revealed that maintenance of HSH2 requires translocation of NF-κB to the nucleus. Because HSH2 mRNA levels are not altered under any conditions, it is hypothesized that NF-κB indirectly regulates the function of a short-lived protease that regulates HSH2 expression at the protein. These results reveal a potentially novel mechanism, in which NF-κB regulates HSH2 expression via one or more proteases and may represent a novel paradigm for controlling GC B cell function.