The Immunological Function Of The Cell Cycle Regulator DCAF2 In Dendritic Cell

The E3 ligase CRL4^DCAF2 is believed to be a pivotal regulator of the cell cycle and required for mitotic and S phase progression.CRL4 serves as an E3 ubiquitin ligase and interacts with different adaptor proteins(named as DCAFs)to recruit their specific substrates.DCAF2(also called CDT2 or DTL)is one of the adaptor proteins of CRL4.As a well studied cell cycle regulator,CRL4^DCAF2ensures the progression of S phage and mitosis stage.CRL4^DCAF2 promotes ubiquitination and degradation of chromatin replication initiation proteins(CDT1,SETD8)and cyclin-dependent kinase inhibitor p21,thereby promoting cell cycle from S phase into G2 phase.However,due to the lack of feasible animal models,the function of CRL4^DCAF2 in vivo,especially in the immune system,is still unknown.External stimuliation have different effects on cell cycle progression in innate lymphocytes and in adaptive immune cells.T cells undergo multiple cell cycles to proliferate rapidly after receiving TCR and co-stimulatory molecular signals.When activated by pattern recognition receptor signals,dendritic cells withdraw the cell cycle and initiate the apoptosis process.As a regulator of S/G2phase transition,the expression of DCAF2 in activated dendritic cells decreases rapidly.The NEDD8-targeting drug MLN4924,which inactivates cullin ring-finger ubiquitin ligases(CRLs),has been examined in therapeutic clinical trials for various types of lymphoma and acute myeloid leukemia.MLN4924 treatment promotes the severity of the mouse psoriasis model,which is consistent with the phenotype caused by the depletion of DCAF2 in dendritic cells,indicating that DCAF2 has an important negative regulatory function in autoimmune diseases.Through transcriptomic approaches,we found that the loss of DCAF2 in dendritic cells specifically increases in the expression of pro-inflammatory cytokine IL-23.Furthermore,we found that CRL4^DCAF in dendritic cells is critical for the protein stability of noncanonical NF-?B factor NIK,which in turn regulates the production of IL-23.CRL4^DCAF2 promotes the polyubiquitination and subsequent degradation of NIK.Interestingly,this process is independent of the classic TRAF2 or TRAF3-mediated NIK degradation signals. Compared with their WT littermates,aging DCAF2 conditional knock-out mice showed a tendency for autoimmune diseases and displayed increased sensitivity to Aldara- induced psoriasis-like skin inflammation model and experimental autoimmune encephalomyelitis model.Our study showed that CRL4^DCAF2 not only serve as a cell cycle regulator,but also control the stability of the noncanonical NF-?B factor NIK in innate immune cells.Our results revealed the specific CRL4^DCAF2regulation of pro-inflammatory cytokine IL-23and the molecular mechanism of CRL4^DCAF2in leading autoimmune diseases in dendritic cells.These results not only greatly advance the field,but and also have profound implications for therapeutic approaches for autoimmune diseases.