SEF/IL-17R (SEFIR) Is Not Enough AN EXTENDED SEFIR DOMAIN IS REQUIRED FOR IL-17RA-MEDIATED SIGNAL TRANSDUCTION
SEF/IL-17R (SEFIR) Is Not Enough AN EXTENDED SEFIR DOMAIN IS REQUIRED FOR IL-17RA-MEDIATED SIGNAL TRANSDUCTION
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DOI：
10.1074/jbc.m110.121418
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发表时间：
2010-10-22
影响因子：
4.8
通讯作者：
Gaffen, Sarah L.
中科院分区：
文献类型：
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作者：
Onishi, Reiko M.;Park, Sangmi J.;Gaffen, Sarah L.
IL-17是Th 17群体的标志性细胞因子，介导对细胞外病原体的免疫并促进自身免疫免疫病理学。由IL-17受体（IL-17 RA）和相关受体触发的信号传导机制与其他细胞因子亚类显著不同。也就是说，IL-17 R含有一个保守的SEF/IL-17 R（SEFIR）亚结构域，该亚结构域与Act 1结合，导致TRAF 6、NF-κ B和其他事件的激活。尽管SEFIR对于信号传导是关键的，但是IL-17 RA内的功能亚结构域的分子细节仍然很难表征。在这里，我们提供了一个详细的结构-功能分析描绘的C-末端边界的SEFIR含有IL-17 RA的区域。我们表明，这个域的功能需要一个大的扩展到以前确定的SEFIR基序。与SEFIR相反，该延伸在IL-17 R家族成员中不保守。令人惊讶的是，Act 1的募集不足以激活下游信号，而TRAF 6的泛素化与功能性受体密切相关。我们进一步证明，IL-17 RA表现出与其他IL-17 R家族成员非冗余的信号传导特性。最后，我们报告说，IL-17信号协同与α 3，使用IL-17 RA内相同的信号基序。这些研究为IL-17 RA的结构-功能关系提供了新的见解，并揭示了IL-17 R家族成员之间的明显信号差异。
IL-17, the hallmark cytokine of the Th17 population, mediates immunity to extracellular pathogens and promotes autoimmune immunopathology. The signaling mechanisms triggered by the IL-17 receptor (IL-17RA) and related receptors are strikingly different from other cytokine subclasses. Namely, IL-17Rs contain a conserved SEF/IL-17R (SEFIR) subdomain that engages Act1, leading to activation of TRAF6, NF-kappa B, and other events. Although the SEFIR is critical for signaling, the molecular details of the functional subdomains within IL-17RA remain poorly characterized. Here, we provide a detailed structure-function analysis delineating the C-terminal boundary of the SEFIR-containing region of IL-17RA. We show that functionality of this domain requires a large extension to the previously identified SEFIR motif. In contrast to the SEFIR, this extension is not conserved among IL-17R family members. Surprisingly, Act1 recruitment is not sufficient for downstream signaling activation, whereas ubiquitination of TRAF6 correlates tightly with functional receptors. We further demonstrate that IL-17RA exhibits signaling properties that are nonredundant with other IL-17R family members. Finally, we report that IL-17 signals synergistically with lymphotoxin-alpha 3, using the same signaling motifs within IL-17RA. These studies provide new insight into the structure-function relationships of IL-17RA and reveal distinct signaling differences among IL-17R family members.