ArticleCellular & molecular immunology2021
CUL4B negatively regulates Toll-like receptor-triggered proinflammatory responses by repressing Pten transcription.
Article in Cellular & molecular immunology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 28 citations in OpenAlex.
- Integrative multi-omics reveals CUL4B as a modulator of macrophage pyroptosis and innate defense againstScience advances · 2026Article
- mTORC2 Phosphorylation of GSDME-N Drives Cullin4B-Mediated Proteasomal Degradation to Suppress Pyroptosis and Confer Radioresistance in Small Cell Lung Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- STING signaling in vestibular macrophages underlies Ménière's disease pathogenesis.Journal of neuroinflammation · 2026Article
- Harnessing Distinct Tissue-Resident Immune Niches via S100A9/TLR4 Improves Ketone, Lipid, and Glucose Metabolism.Endocrinology · 2025Article
- The role of gut-islet axis in pancreatic islet function and glucose homeostasis.Diabetes, obesity & metabolism · 2025Review
- Targeting persistently activated inflammatory microenvironment to promote chronic wound healing.Frontiers in immunology · 2025Review
- Elucidating the immunomodulatory roles and mechanisms of CUL4B in the immune system: a comprehensive review.Frontiers in immunology · 2025Review
- CUL4B protects kidneys from acute injury by restraining p53/PAI-1 signaling.Cell death & disease · 2024Article
- The Cullin-RING Ligase Family in Immune Regulation.Advances in experimental medicine and biology · 2024Review
- Cullin 4B-RING E3 ligase complex in immune cell differentiation and function.Cellular & molecular immunology · 2023Article
- CRL4B complex-mediated H2AK119 monoubiquitination restrains Th1 and Th2 cell differentiation.Cell death and differentiation · 2023Article
- Identification of different proteins binding to Na, K-ATPase α1 in LPS-induced ARDS cell model by proteomic analysis.Proteome science · 2022Article
- Comprehensive analysis of NCancer cell international · 2022Article
- ACK1 Contributes to the Pathogenesis of Inflammation and Autoimmunity by Promoting the Activation of TLR Signaling Pathways.Frontiers in immunology · 2022Article
- CUL4B is a Potential Novel Prognostic Biomarker and is Correlated with Immune Infiltrates in Malignant Pleural Mesothelioma.International journal of general medicine · 2022Article
- Aberrant expression of miR-199a in newborns with hypoxic-ischemic encephalopathy and its diagnostic and prognostic significance when combined with S100B and NSE.Acta neurologica Belgica · 2021Article
- Neurodevelopmental Disorders (NDD) Caused by Genomic Alterations of the Ubiquitin-Proteasome System (UPS): the Possible Contribution of Immune Dysregulation to Disease Pathogenesis.Frontiers in molecular neuroscience · 2021Review
- Phosphatase and Tensin Homolog in Non-neoplastic Digestive Disease: More Than Just Tumor Suppressor.Frontiers in physiology · 2021Review
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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 GSK3β activity. Suppression of GSK3β 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-GSK3β pathway. The upregulation of PTEN caused by CUL4B deletion led to uncontrolled GSK3β activity and excessive inflammatory immune responses. Thus, our findings indicate that CUL4B functions to restrict TLR-triggered inflammatory responses through regulating the AKT-GSK3β pathway.
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