A critical role for neddylation in regulating dendritic cell function. (P1369)

Abstract

Abstract Post-translational modifications (PTMs) of proteins modulate cellular processes. However, the role, specifically that of neddylation (a type of PTM), in regulating immune cells is not known. Neddylation of Cullin-RING ligase (CRL) protein modulates the process of ubiquitination. Thus, CRL activity is critical for the quotidian functions of cells. We explored the role of neddylation in dendritic cells (DCs) utilizing the small molecule inhibitor of neddylation (MLN4924) and the knockdown of SAG, a critical adapter element of CRL. Inhibition of neddylation in the DC significantly reduced the expression and release of several proinflammatory cytokines (TNFα, IL-6) and significantly reduced the ability of DCs to stimulate T cells (P<0.001) following stimulation by several TLR and NLR ligands. This suppression of DC functions was more than that caused by the known anti-inflammatory drug dexamethasone. Mechanistic studies showed that reduction of IκB degradation was critical for the suppression of DCs by the inhibitors of neddylation. This was further confirmed by the absence of NF-κB translocation and function. However, MAPK/ERK pathway was unperturbed by the inhibition of neddylation. Our results demonstrate a novel biological role of inhibition of the PTM, neddylation, in regulating DC functions.