Department of Orthopaedic Surgery, New York University Medical Center, New York, NY 10003, United States.
FEBS Lett. 2013 Nov 1;587(21):3428-36. doi: 10.1016/j.febslet.2013.09.024. Epub 2013 Sep 23.
We previously reported that PGRN directly bound to TNF receptors (TNFR) in vitro and in chondrocytes (Tang, et al., Science, 2011). Here we report that PGRN also associated with TNFR in splenocytes, and inhibited the binding of TNFα to immune cells. Proper folding of PGRN is essential for its binding to TNFR, as DTT treatment abolished its binding to TNFR. In contrast, the binding of PGRN to Sortilin was enhanced by DTT. Protein interaction assays with mutants of the TNFR extracellular domain demonstrated that CRD2 and CRD3 of TNFR are important for the interaction with PGRN, similar to the binding to TNFα. Taken together, these findings provide the molecular basis underlying PGRN/TNFR interaction and PGRN-mediated anti-inflammatory activity in various autoimmune diseases and conditions.
我们之前报道过，PGRN 可在体外和软骨细胞中直接与 TNF 受体（TNFR）结合（Tang 等人，《科学》，2011 年）。在这里，我们报告 PGRN 也与脾细胞中的 TNFR 相关联，并抑制 TNFα 与免疫细胞的结合。PGRN 正确折叠对于与 TNFR 结合至关重要，因为 DTT 处理会使其丧失与 TNFR 的结合能力。相比之下，PGRN 与 Sortilin 的结合会因 DTT 而增强。使用 TNFR 细胞外结构域的突变体进行蛋白相互作用测定表明，CRD2 和 CRD3 是 TNFR 与 PGRN 相互作用的重要结构域，类似于与 TNFα 的结合。综上所述，这些发现为 PGRN/TNFR 相互作用以及 PGRN 在各种自身免疫性疾病和病症中的抗炎活性提供了分子基础。
