Wu Dennis J, Adamopoulos Iannis E
Graduate Group in Immunology, University of California at Davis, USA; Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, USA.
Graduate Group in Immunology, University of California at Davis, USA; Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, USA; Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Northern California, USA.
Cell Immunol. 2017 Jun;316:61-69. doi: 10.1016/j.cellimm.2017.04.001. Epub 2017 Apr 22.
WDFY3 is a master regulator of selective autophagy that we recently showed to interact with TRAF6 and augment RANKL-induced osteoclastogenesis in vitro and in vivo via the NF-κB pathway. Since the NF-κB pathway plays a major role in inflammation herein, we investigate the role of WDFY3 in an arthritis animal model. Our data show that WDFY3 conditional knockout mice (Wdfy3-LysM-Cre+) were protected in the K/BxN serum transfer-induced arthritis animal model. These effects were independent of alterations in starvation-induced autophagy as evidenced by Western blot analysis of the autophagy marker LC3, autophagosome formation in osteoclast precursors and lysosome formation in osteoclasts derived from WDFY3-cKO mice compared to controls. Moreover, we demonstrate by immunofluorescence and co-immunoprecipitation that WDFY3 interacts with SQSTM1 in macrophages and osteoclasts. Collectively, our data suggest that loss of WDFY3 in myeloid cells leads to reduced severity of inflammatory arthritis independently of WDFY3 function in starvation-induced autophagy.
WDFY3是选择性自噬的主要调节因子，我们最近发现它与TRAF6相互作用，并通过NF-κB途径在体外和体内增强RANKL诱导的破骨细胞生成。由于NF-κB途径在本文所述的炎症中起主要作用，我们研究了WDFY3在关节炎动物模型中的作用。我们的数据表明，在K/BxN血清转移诱导的关节炎动物模型中，WDFY3条件性敲除小鼠（Wdfy3-LysM-Cre+）受到保护。与对照组相比，通过对自噬标志物LC3的蛋白质印迹分析、破骨细胞前体中的自噬体形成以及源自WDFY3-cKO小鼠的破骨细胞中的溶酶体形成证明，这些作用与饥饿诱导的自噬改变无关。此外，我们通过免疫荧光和免疫共沉淀证明WDFY3在巨噬细胞和破骨细胞中与SQSTM1相互作用。总体而言，我们的数据表明，髓系细胞中WDFY3的缺失导致炎症性关节炎的严重程度降低，这与WDFY3在饥饿诱导的自噬中的功能无关。
