On July 17, 2018, Jin Jin Lab published a research paper on JEM entitled “ CRL4DCAF2 negatively regulates IL-23 production in dendritic cells and limits the development of psoriasis ”. This article reveal CRL4DCAF2 as a pivotal regulator of noncanonical NF-κB signaling and autoimmune responses.
The E3 ligase CRL4DCAF2 is believed to be a pivotal regulator of the cell cycle and is required for mitotic and S phase progression. For example, CRL4DCAF2 can promote the ubiquitin-dependent destruction of the replication initiation protein CDT1, SETD8, and the cyclin-dependent kinase inhibitor p21. But its in vivo functions ，especially those in the immune system,are largely unknown due to the lack of viable animal models.
The NEDD8-targeting drug MLN4924, which inactivates cullin ring-fnger ubiquitin ligases (CRLs), has been examined in clinical trials for various types of lymphoma and acute myeloid leukemia. MLN4924 treatment, which mimics DCAF2 depletion, also promotes the severity of mouse psoriasis models, consistent with the effects of reduced DCAF2 expression in various autoimmune diseases. This phenomenon indicates that DCAF2 has an important function in autoimmune diseases. Using transcriptomic and immunological approaches, we showed that CRL4DCAF2 in dendritic cells (DCs) regulates the proteolytic fate of NIK and negatively regulates IL-23 production. CRL4DCAF2 promoted the polyubiquitination and subsequent degradation of NIK independent of TRAF3 degradation. DCAF2 defciency facilitated NIK accumulation and RelB nuclear translocation. DCAF2 DC-conditional knockout mice displayed increased sensitivity to autoimmune diseases. Tis study shows that CRL4DCAF2 is crucial for controlling NIK stability and highlights a unique mechanism that controls inflammatory diseases.
Figure 1 The molecular mechanism of DCAF2 regulating IL-23 production and psoriasis. Deregulated NF-kB activation is linked to immunological disorders. CRL4DCAF2 as a negative regulator in controlling NIK stability in DCs. Lower level of DCAF2 is associated with noncanonical NF-kB activation and hyperproduction of IL-23 in psoriasis patients.
Ph.D. students Huan Tao and Gao Zhengjun in Dr. Jin’s group are co-first authors. Dr. Jin is the corresponding author of this article.This work was supported by the National Natural Science Foundation of China, the Fundamental Research Funds for the Central Universities, the National Natural Science Foundation of China, the Thousand Young Talents Plan of China, and the Zhejiang University Special Fund for Fundamental Research.
Link：http://jem.rupress.org/content/early/2018/07/16/jem.20180210
