The ASCIZ-DYNLL1 Axis Is Essential for TLR4-Mediated Antibody Responses and NF-κB Pathway Activation

Abstract

Toll-like receptors (TLRs) and IL-1 receptors regulate immune and inflammatory responses by activating the nuclear factor (NF)-κB pathway. Here we report that B cell-specific loss of Dynein light chain-1 (DYNLL1, LC8) or its designated transcription factor ASCIZ (ATMIN) leads to severely reduced in vivo antibody responses to TLR4-dependent but not T cell-dependent antigens in mice. This defect was independent of DYNLL1’s established roles in modulating BIM-dependent apoptosis and 53BP1-dependent antibody class-switch recombination. In B cells and fibroblasts, the ASCIZ-DYNLL1 axis was required for TLR4-, IL-1- and CD40-mediated NF-κB pathway activation but dispensable for antigen receptor and TNF-α signalling. In contrast to previous reports that overexpressed DYNLL1 directly inhibits the phosphorylation and degradation of the NF-κB inhibitor IκBα, we found here that - under physiological conditions - DYNLL1 is required for signal-specific activation of the NF-κB pathway upstream of IκBα. Our data identify DYNLL1 as a signal-specific regulator of the NF-κB pathway and indicate that it may act as a universal modulator of TLR4 (and IL-1) signalling with wide-ranging roles in inflammation and immunity.