Projects per year
Abstract
Toll-like receptors (TLRs) and interleukin-1 (IL-1) receptors regulate immune and inflammatory responses by activating the NF-kB 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-kB pathway activation but dispensable for antigen receptor and tumor necrosis factor a (TNF-a) signaling. In contrast to previous reports that overexpressed DYNLL1 directly inhibits the phosphorylation and degradation of the NF-kB inhibitor IkBa, we found here that under physiological conditions, DYNLL1 is required for signal-specific activation of the NF-kB pathway upstream of IkBa. Our data identify DYNLL1 as a signal-specific regulator of the NF-kB pathway and indicate that it may act as a universal modulator of TLR4 (and IL-1) signaling with wide-ranging roles in inflammation and immunity.
Original language | English |
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Article number | e00251-21 |
Number of pages | 14 |
Journal | Molecular and Cellular Biology |
Volume | 41 |
Issue number | 12 |
DOIs | |
Publication status | Published - Nov 2021 |
Keywords
- B-cell responses
- BIM
- Cell proliferation
- DYNLL1
- Immunization
- NF-kB
Projects
- 1 Finished
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NHMRC Principal Research Fellowship
National Health and Medical Research Council (NHMRC) (Australia)
11/01/16 → 31/12/19
Project: Research