CCDC88B is a risk factor for several chronic inflammatory diseases in humans and its inactivation causes a migratory defect in DCs in mice. CCDC88B belongs to a family of cytoskeleton-associated scaffold proteins that feature protein:protein interaction domains. Here, we identified the Rho/Rac Guanine Nucleotide Exchange Factor 2 (ARHGEF2) and the RAS Protein Activator Like 3 (RASAL3) as CCDC88B physical and functional interactors. Mice defective in Arhgef2 or Rasal3 show dampened neuroinflammation, and display altered cellular response and susceptibility to colitis; ARHGEF2 maps to a human Chromosome 1 locus associated with susceptibility to IBD. Arhgef2 and Rasal3 mutant DCs show altered migration and motility in vitro, causing either reduced (Arhgef2) or enhanced (Rasal3) migratory properties. The CCDC88B/RASAL3/ARHGEF2 complex appears to regulate DCs migration by modulating activation of RHOA, with ARHGEF2 and RASAL3 acting in opposite regulatory fashions, providing a molecular mechanism for the involvement of these proteins in DCs immune functions.

CCDC88B是人类多种慢性炎症性疾病的危险因素，其失活会导致小鼠 DC 的迁移缺陷。 CCDC88B 属于细胞骨架相关支架蛋白家族，具有蛋白质：蛋白质相互作用域。在这里，我们将 Rho/Rac 鸟嘌呤核苷酸交换因子 2 (ARHGEF2) 和 RAS 蛋白激活剂样 3 (RASAL3) 确定为 CCDC88B 物理和功能相互作用因子。 Arhgef2 或 Rasal3缺陷的小鼠表现出神经炎症减弱，并表现出细胞反应改变和对结肠炎的易感性改变； ARHGEF2映射到与 IBD 易感性相关的人类 1 号染色体位点。 Arhgef2和Rasal3突变 DC 在体外显示出改变的迁移和运动性，导致迁移特性降低 ( Arhgef2 ) 或增强 ( Rasal3 )。 CCDC88B/RASAL3/ARHGEF2 复合物似乎通过调节 RHOA 的激活来调节 DC 迁移，其中 ARHGEF2 和 RASAL3 以相反的调节方式发挥作用，为这些蛋白参与 DC 免疫功能提供了分子机制。