CRL4DCAF2 negatively regulates IL-23 production in dendritic cells and limits the development of psoriasis

Author:

Huang Tao1,Gao Zhengjun1,Zhang Yu2,Fan Keqi1,Wang Fei1,Li Yiyuan1,Zhong Jiangyan1,Fan Heng Y.1,Cao Qian2,Zhou Jiyong3,Xiao Yichuan4ORCID,Hu Hongbo5ORCID,Jin Jin13ORCID

Affiliation:

1. Life Sciences Institute, Zhejiang University, Hangzhou, China

2. Sir Run Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou, China

3. Key Laboratory of Animal Virology of Ministry of Agriculture, Zhejiang University, Hangzhou, China

4. Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, Shanghai, China

5. Department of Rheumatology and Immunology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, China

Abstract

The E3 ligase CRL4DCAF2 is believed to be a pivotal regulator of the cell cycle and is required for mitotic and S phase progression. The NEDD8-targeting drug MLN4924, which inactivates cullin ring-finger ubiquitin ligases (CRLs), has been examined in clinical trials for various types of lymphoma and acute myeloid leukemia. However, the essential role of CRL4DCAF2 in primary myeloid cells remains poorly understood. 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. 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 deficiency facilitated NIK accumulation and RelB nuclear translocation. DCAF2 DC-conditional knockout mice displayed increased sensitivity to autoimmune diseases. This study shows that CRL4DCAF2 is crucial for controlling NIK stability and highlights a unique mechanism that controls inflammatory diseases.

Funder

National Key Research and Development Program of China

National Natural Science Foundation of China

Fundamental Research Funds for the Central Universities

Thousand Young Talents Plan of China

Zhejiang University

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3