Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany.
PLoS One. 2012;7(7):e41255. doi: 10.1371/journal.pone.0041255. Epub 2012 Jul 19.
NOD2, the nucleotide-binding domain and leucine-rich repeat containing gene family (NLR) member 2 is involved in mediating antimicrobial responses. Dysfunctional NOD2 activity can lead to severe inflammatory disorders, but the regulation of NOD2 is still poorly understood. Recently, proteins of the tripartite motif (TRIM) protein family have emerged as regulators of innate immune responses by acting as E3 ubiquitin ligases. We identified TRIM27 as a new specific binding partner for NOD2. We show that NOD2 physically interacts with TRIM27 via the nucleotide-binding domain, and that NOD2 activation enhances this interaction. Dependent on functional TRIM27, ectopically expressed NOD2 is ubiquitinated with K48-linked ubiquitin chains followed by proteasomal degradation. Accordingly, TRIM27 affects NOD2-mediated pro-inflammatory responses. NOD2 mutations are linked to susceptibility to Crohn's disease. We found that TRIM27 expression is increased in Crohn's disease patients, underscoring a physiological role of TRIM27 in regulating NOD2 signaling. In HeLa cells, TRIM27 is partially localized in the nucleus. We revealed that ectopically expressed NOD2 can shuttle to the nucleus in a Walker A dependent manner, suggesting that NOD2 and TRIM27 might functionally cooperate in the nucleus.We conclude that TRIM27 negatively regulates NOD2-mediated signaling by degradation of NOD2 and suggest that TRIM27 could be a new target for therapeutic intervention in NOD2-associated diseases.
核苷酸结合结构域和富含亮氨酸重复序列的寡核苷酸结合蛋白 2（NOD2）属于核苷酸结合结构域和富含亮氨酸重复序列的寡核苷酸结合蛋白家族（NLR）成员，其参与了调控抗菌反应。NOD2 功能障碍可能导致严重的炎症性疾病，但 NOD2 的调控机制仍知之甚少。最近，三部分基序（TRIM）蛋白家族的蛋白已被证明可以作为 E3 泛素连接酶来调节先天免疫反应。我们鉴定了 TRIM27 是 NOD2 的新的特定结合伴侣。我们表明，NOD2 通过核苷酸结合域与 TRIM27 发生物理相互作用，并且 NOD2 的激活增强了这种相互作用。依赖于功能正常的 TRIM27，异位表达的 NOD2 被 K48 连接的泛素链泛素化，随后被蛋白酶体降解。因此，TRIM27 影响 NOD2 介导的促炎反应。NOD2 突变与克罗恩病易感性相关。我们发现，TRIM27 在克罗恩病患者中的表达增加，这突显了 TRIM27 在调控 NOD2 信号中的生理作用。在 HeLa 细胞中，TRIM27 部分定位于细胞核内。我们揭示了异位表达的 NOD2 可以以 Walker A 依赖的方式穿梭到细胞核内，表明 NOD2 和 TRIM27 可能在细胞核内发挥功能协同作用。我们的结论是，TRIM27 通过降解 NOD2 负调控 NOD2 介导的信号转导，并提示 TRIM27 可能成为 NOD2 相关疾病治疗干预的新靶点。
