Cullin 4B-RING E3 ligase complex in immune cell differentiation and function

CUL4B,which encodes the scaffold protein in the CRL4B complex,is a commonly mutated gene in X-linked intellectual disability[10,11].In addition to intellectual disability,patients with CUL4B mutations present with an elevated number of monocytes in peripheral blood[10],implying a role for CUL4B in regulating monocytes/macrophages.Monocytes/macrophages are critical players in innate immunity.Hung et al.found that depletion of CUL4B in myeloid cells aggravated lipopolysaccharide(LPS)-induced acute peritonitis[3].They further showed that after LPS stimulation,Cul4b-deficient macrophages secreted more chemokines than control macrophages,which might have accounted for the elevated infiltration of immune cells into the peritoneum[3].Our previous work demonstrated that myeloid-specific Cul4b-knockout mice exhibited reduced survival after LPS injection or Salmonella typhimurium infection compared to control mice[6].In contrast to work from Hung et al.,which showed that Cul4b-deficient macrophages secreted less TNFαand IL-6 after LPS stimulation[3],our works showed that deletion of CUL4B in macrophages increased the production of proinflammatory cytokines and decreased the expression of the anti-inflammatory cytokine IL-10 in response to the activation of Toll-like receptor(TLR).CUL4B regulation of macrophages relies on the ubiquitination activity of the CRL4B complex.The CRL4B complex catalyzes monoubiquitination of H2AK119 at the promoter of Pten,resulting in the repression of Pten transcription and subsequent activation of AKT and AKT-dependent inhibition of GSK3β,which suppresses TLR-triggered proinflammatory responses(Fig.1B)[6].