Figure 8.

A representative model of CRL4A^DCAF8 E3 ligase-mediated signaling in the pathogenesis of SIMD. CRL4A^DCAF8 E3 ligase-mediated signaling in the pathogenesis of SIMD can be divided into two steps. In the first step, CUL4A associates with RBX1, DDB1 and DCAF8 to form the CRL4A^DCAF8 E3 ligase complex, which recognizes NcoR1 as a substrate, leading to degradation in the pathogenesis of SIMD. The degraded NcoR1 cannot function effectively as a corepressor to inhibit SP1-mediated transcription, causing the upregulation of HMGB1. In the second step, mature HMGB1 in the extracellular membrane binds to TLR4 to initiate downstream events, leading to the activation of a cascade that includes TIRAP, MyD88, IRAK1, IRAK4, TRAF6, TAK1 and IKKs. The phosphorylation of IκB mediated by IKKs impairs its inhibition of NF-κB, leading to the release and translocation of NF-κB. In the nucleus, NF-κB induces the expression of proinflammatory genes and results in an inflammatory response, leading to the pathogenesis of SIMD. The small molecule PSSM0332 specifically disrupts the CUL4A-RBX1 interaction, impairing the assembly of the CRL4^DCAF8 E3 ligase complex and affecting downstream events, eventually improving the inflammatory response and alleviating the SIMD outcome.