Epithelial CRL4DCAF2 is critical for mucosal repair in intestine

The intestinal epithelium has one of the highest rates of cellular turnover in a process that is tightly regulated. An aberrant increase in the rate of intestinal epithelial cell (IEC) death underlies instances of extensive epithelial erosion, which is characteristic of several intestinal diseases such as inflammatory bowel disease(IBD) and infectious colitis. The E3 ligase CRL4DCAF2 is believed to be a pivotal regulator of the cell cycle. Here we found that DCAF2 expression was significantly decreased in UC patients. Mice with intestinal epithelial-specific knockout of DCAF2 might suffer from embryonic death. DCAF2 IEC-conditional knockdown mouse displayed more severe inflammation presentations in DSS-induced colitis model. Using transcriptomic approaches, we showed that CRL4DCAF2 in IECs regulates the intestine barriar and positively regulates DNA replication.CRL4DCAF2 promoted the proliferation of IEC. DCAF2 deficiency facilitated apoptosis protein accumulation .we also revealed that CRL4DCAF2 may reduce the symptoms of colitis by maintaining the stability of autophagy. MLN4924 treatment, which mimics DCAF2 depletion, also promotes the severity of mouse colitis models. This study shows that CRL4DCAF2 is crucial for intestine barriar stability and highlights a unique mechanism protein ubiquitination in the pathogenesis and development of IBD.

肠道上皮是体内细胞更新速率最高的组织之一，其更新过程受到严格调控。肠上皮细胞（intestinal epithelial cell, IEC）死亡速率异常升高是广泛性上皮糜烂的核心病理机制，而该特征常见于炎症性肠病（inflammatory bowel disease, IBD）、感染性结肠炎等多种肠道疾病。E3泛素连接酶（E3 ligase）CRL4DCAF2被认为是细胞周期的关键调控因子。本研究发现，溃疡性结肠炎（Ulcerative Colitis, UC）患者体内DCAF2的表达水平显著下调。肠上皮特异性敲除DCAF2的小鼠可出现胚胎致死现象。肠上皮细胞条件性敲低DCAF2的小鼠，在葡聚糖硫酸钠（dextran sulfate sodium, DSS）诱导的结肠炎模型中表现出更严重的炎症表型。通过转录组学分析，我们证实肠上皮细胞中的CRL4DCAF2可调控肠道屏障功能，并正向调控DNA复制过程。CRL4DCAF2可促进肠上皮细胞的增殖。DCAF2缺失会促进凋亡相关蛋白的积累。本研究还发现，CRL4DCAF2可通过维持自噬稳态减轻结肠炎症状。模拟DCAF2缺失的MLN4924处理，同样会加重小鼠结肠炎模型的病情严重程度。本研究证实CRL4DCAF2对肠道屏障稳态至关重要，并揭示了蛋白质泛素化在炎症性肠病发病与进展中的独特调控机制。