Free IL-12p40 monomer is a polyfunctional adaptor for generating novel IL-12-like heterodimers extracellularly.
Free IL-12p40 monomer is a polyfunctional adaptor for generating novel IL-12-like heterodimers extracellularly.
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DOI：
10.4049/jimmunol.1400159
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发表时间：
2014-06-15
期刊：
影响因子：
--
通讯作者：
Ploegh HL
中科院分区：
文献类型：
--
作者：
Abdi K;Singh NJ;Spooner E;Kessler BM;Radaev S;Lantz L;Xiao TS;Matzinger P;Sun PD;Ploegh HL
IL-12 p40与p35和p19多肽配对以分别产生异二聚体细胞因子IL-12和IL-23。这些细胞因子在宿主防御中发挥关键和独特的作用。这些异源二聚体的组装被认为发生在细胞内，导致全功能细胞因子的分泌。虽然单独的p40亚基也可以响应炎症信号而快速分泌，但其生物学意义仍不清楚。在这里，我们表明，分泌的p40单体可以产生从头IL-12样活动相结合的细胞外从其他细胞释放的p35。令人惊讶的是，一个公正的蛋白质组学分析揭示了多个这样的细胞外结合伴侣的p40在小鼠血清中的内毒素攻击后。我们的生物化学验证这些新的合作伙伴之一的CD 5抗原样糖蛋白CD 5L的p40单体的结合。然而，组装的p40-CD 5L异源二聚体并不概括IL-12的生物活性。这些发现强调了分泌的游离p40单体的可塑性，表明p40作为一种衔接子发挥作用，能够在分泌后与其他局部可用的多肽伴侣结合产生多种从头复合物。
IL-12p40 partners with the p35 and p19 polypeptides to generate the heterodimeric cytokines IL-12 and IL-23 respectively. These cytokines play critical and distinct roles in host defense. The assembly of these heterodimers is thought to take place within the cell, resulting in the secretion of fully functional cytokines. Although the p40 subunit alone can also be rapidly secreted in response to inflammatory signals, its biological significance remains unclear. Here, we show that the secreted p40 monomer can generate de novo IL-12-like activities by combining extracellulary with p35 released from other cells. Surprisingly, an unbiased proteomic analysis reveals multiple such extracellular binding partners for p40 in the serum of mice after an endotoxin challenge. We biochemically validate the binding of one of these novel partners—the CD5 antigen-like glycoprotein CD5L— to the p40 monomer. Nevertheless, the assembled p40-CD5L heterodimer does not recapitulate the biological activity of IL-12. These findings underscore the plasticity of secreted free p40 monomer, suggesting that p40 functions as an adapter which is able to generate multiple de novo composites in combination with other locally available polypeptide partners, post secretion.
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