CUL4B negatively regulates Toll-like receptor-triggered proinflammatory responses by repressing Pten transcription

Toll-like receptors (TLRs) play critical roles in innate immunity and inflammation. The molecular mechanisms by which TLR signaling is fine-tuned remain to be completely elucidated. Cullin 4B (CUL4B), which assembles the CUL4B-RING E3 ligase complex (CRL4B), has been shown to regulate diverse developmental and physiological processes by catalyzing monoubiquitination for histone modification or polyubiquitination for proteasomal degradation. Here, we identified the role of CUL4B as an intrinsic negative regulator of the TLR-triggered inflammatory response. Deletion of CUL4B in macrophages increased the production of proinflammatory cytokines and decreased anti-inflammatory cytokine IL-10 production in response to pathogens that activate TLR3, TLR4, or TLR2. Myeloid cell-specific Cul4b knockout mice were more susceptible to septic shock when challenged with lipopolysaccharide, polyinosinic-polycytidylic acid or Salmonella typhimurium infection. We further demonstrated that enhanced TLR-induced inflammatory responses in the absence of CUL4B were mediated by increased GSK3 beta activity. Suppression of GSK3 beta activity efficiently blocked the TLR-triggered increase in proinflammatory cytokine production and attenuated TLR-triggered death in Cul4b mutant mice. Mechanistically, CUL4B was found to negatively regulate TLR-triggered signaling by epigenetically repressing the transcription of Pten, thus maintaining the anti-inflammatory PI3K-AKT-GSK3 beta pathway. The upregulation of PTEN caused by CUL4B deletion led to uncontrolled GSK3 beta activity and excessive inflammatory immune responses. Thus, our findings indicate that CUL4B functions to restrict TLR-triggered inflammatory responses through regulating the AKT-GSK3 beta pathway.

Automated summary

CUL4B functions as an intrinsic negative regulator of the TLR-triggered inflammatory response, enhancing proinflammatory cytokine production and reducing anti-inflammatory cytokine IL-10 production when deleted in macrophages. Enhanced TLR-induced inflammatory responses in the absence of CUL4B are mediated by increased GSK3β activity. By regulating the PI3K-AKT-GSK3β pathway, CUL4B restricts TLR-triggered inflammatory responses.