Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, IN 47907-1243, USA.
J Cell Mol Med. 2012 Oct;16(10):2271-9. doi: 10.1111/j.1582-4934.2012.01574.x.
Mice with spontaneous mutations in the Sharpin gene develop chronic proliferative dermatitis that is characterized by eosinophilic inflammation of the skin and other organs with increased expression of type 2 cytokines and dysregulated development of lymphoid tissues. The mutant mice share phenotypic features with human hypereosinophilic syndromes. The biological function of SHARPIN and how its absence leads to such a complex inflammatory phenotype in mice are poorly understood. However, recent studies identified SHARPIN as a novel modulator of immune and inflammatory responses. The emerging mechanistic model suggests that SHARPIN functions as an important adaptor component of the linear ubiquitin chain assembly complex that modulates activation of NF-κB signalling pathway, thereby regulating cell survival and apoptosis, cytokine production and development of lymphoid tissues. In this review, we will summarize the current understanding of the ubiquitin-dependent regulatory mechanisms involved in NF-κB signalling, and incorporate the recently obtained molecular insights of SHARPIN into this pathway. Recent studies identified SHARPIN as an inhibitor of β1-integrin activation and signalling, and this may be another mechanism by which SHARPIN regulates inflammation. Furthermore, the disrupted lymphoid organogenesis in SHARPIN-deficient mice suggests that SHARPIN-mediated NF-κB regulation is important for de novo development of lymphoid tissues.
自发性基因突变导致 Sharpin 基因缺失的小鼠会发展为慢性增殖性皮炎，其特征为皮肤和其他器官的嗜酸性粒细胞炎症，2 型细胞因子表达增加，以及淋巴组织发育失调。这些突变小鼠具有人类嗜酸性粒细胞增多综合征的表型特征。SHARPIN 的生物学功能以及其缺失如何导致小鼠出现如此复杂的炎症表型尚不清楚。然而，最近的研究表明 SHARPIN 是一种新型免疫和炎症反应调节剂。新兴的机制模型表明，SHARPIN 作为线性泛素链组装复合物的重要衔接成分，调节 NF-κB 信号通路的激活，从而调节细胞存活和凋亡、细胞因子产生以及淋巴组织发育。在这篇综述中，我们将总结目前对 NF-κB 信号通路中涉及的泛素依赖性调节机制的理解，并将最近获得的关于 SHARPIN 的分子见解纳入该通路。最近的研究表明 SHARPIN 是β1-整合素激活和信号的抑制剂，这可能是 SHARPIN 调节炎症的另一种机制。此外，Sharpin 基因缺失的小鼠中淋巴器官发育不良表明，SHARPIN 介导的 NF-κB 调节对于新生成的淋巴组织发育很重要。
