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

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.

Role of microRNAs As Biomarkers in Sepsis-Associated Encephalopathy

“…In addition, miR-210 is upregulated under hypoxic conditions; therefore, it is considered an important regulator of hypoxia response through the control of many functions such as DNA repair, mitochondrial respiration, angiogenesis, and cell proliferation [ 116 , 117 ]. Likewise, low miR-210 levels have shown neuroprotective effects on mice with hypoxic-ischemic encephalopathy, due to its capacity for activating microglia, so it is upregulated during the development of the pathology [ 118 – 120 ]. Interestingly, miR-210 was related to ROS generation and inflammation in the brain through the ischemia–reperfusion process [ 119 , 121 ].…”

Neurodevelopmental Disorders (NDD) Caused by Genomic Alterations of the Ubiquitin-Proteasome System (UPS): the Possible Contribution of Immune Dysregulation to Disease Pathogenesis

“…It is also understood that the E3 ubiquitin ligases HACE1 (Mao et al, 2016), MID1 (Chen et al, 2021), NEDD4L (Gao et al, 2021), PRKN (Sliter et al, 2018), RNF125 (Arimoto et al, 2007), RNF170 (Song et al, 2020), RNF216 (Nakhaei et al, 2009), STUB1 (Zhou et al, 2018), as well as UBE3A (Furumai et al, 2019) are involved in antiviral innate defense and the generation of type I interferon (IFN) responses (Figure 2). Again, besides NEDD4L, all these genes encode ligases involved in type I IFN negative feedback loops and, as such any dysfunction, would lead to uncontrolled type I IFN responses.…”

“…Strikingly, besides ITCH, more than two-thirds of the E3 ubiquitin ligases reported to cause NDD have critical functions in the innate and adaptive immune systems. As listed in Tables 1 , 2 , the E3 ubiquitin ligases CUL4B ( Hung et al, 2014 ; Song et al, 2021 ), HUWE1 ( Ohtake et al, 2016 ; Guo et al, 2020b ), RNF216 ( Kumazoe et al, 2017 ), STUB1 ( Yang et al, 2011 ), TRAF7 ( Zotti et al, 2011 ), TRIM37 ( Li et al, 2018 ; Zhao et al, 2021 ), CRBN ( Min et al, 2016 ; Yang et al, 2018 ), and the substrate recognition component FBXO7 ( Kuiken et al, 2012 ) have been shown to regulate the expression of inflammatory cytokines mostly thanks to their capacity of modulating NF-κB signaling and/or the inflammasome. It is worth noting that, except HUWE1, all these ligases are described as inflammation negative regulators of these pathways ( Figure 2 ), implying that any loss-of-function of any one of these genes would result in the sustained production of pro-inflammatory cytokines.…”

Phosphatase and Tensin Homolog in Non-neoplastic Digestive Disease: More Than Just Tumor Suppressor

“…Besides, when challenged with Salmonella infection, PTEN was epigenetically suppressed by CUL4B, which negatively regulates the TLR-triggered signaling and maintains the anti-inflammatory pathway PI3K-AKT-glycogen synthase kinase (GSK) 3β. However, overexpression of PTEN caused by CUL4B deletion contributed to excessive activation of GSK3 and uncontrolled immune response, which may increase the risk of septic shock in infected individuals (Song et al, 2021).…”