Slowicka Karolina, Vereecke Lars, Mc Guire Conor, Sze Mozes, Maelfait Jonathan, Kolpe Annasaheb, Saelens Xavier, Beyaert Rudi, van Loo Geert
Inflammation Research Center, Unit of Cellular and Molecular (Patho)physiology, Ghent, Belgium.
Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Eur J Immunol. 2016 Apr;46(4):971-80. doi: 10.1002/eji.201545863. Epub 2016 Jan 15.
Optineurin (OPTN) is an evolutionary conserved and ubiquitously expressed ubiquitin-binding protein that has been implicated in glaucoma, Paget bone disease, amyotrophic lateral sclerosis, and other neurodegenerative diseases. From in vitro studies, OPTN was shown to suppress TNF-induced NF-κB signaling and virus-induced IRF signaling, and was identified as an autophagy receptor required for the clearance of cytosolic Salmonella upon infection. To assess the in vivo functions of OPTN in inflammation and infection, we generated OPTN-deficient mice. OPTN knockout mice are born with normal Mendelian distribution and develop normally without any signs of spontaneous organ abnormality or inflammation. However, no differences in NF-κB activation could be observed in OPTN knockout mice or fibroblasts derived from these mice upon TNF or LPS treatment. Primary bone marrow-derived macrophages from OPTN-deficient mice had slightly impaired IRF signaling and reduced IFN type I production in response to LPS or poly(I,C). Finally, OPTN-deficient mice were more susceptible to infection with Salmonella, confirming in vivo the importance of OPTN in bacterial clearance.
视神经萎缩蛋白（OPTN）是一种进化上保守且广泛表达的泛素结合蛋白，与青光眼、佩吉特骨病、肌萎缩侧索硬化症及其他神经退行性疾病有关。体外研究表明，OPTN可抑制肿瘤坏死因子（TNF）诱导的核因子κB（NF-κB）信号传导以及病毒诱导的干扰素调节因子（IRF）信号传导，并且被确定为感染后清除胞质沙门氏菌所需的自噬受体。为了评估OPTN在炎症和感染中的体内功能，我们培育了OPTN基因缺陷小鼠。OPTN基因敲除小鼠出生时孟德尔分布正常，发育正常，没有任何自发的器官异常或炎症迹象。然而，在TNF或脂多糖（LPS）处理后，OPTN基因敲除小鼠或源自这些小鼠的成纤维细胞中未观察到NF-κB激活的差异。来自OPTN基因缺陷小鼠的原代骨髓来源巨噬细胞在对LPS或聚肌苷酸-聚胞苷酸（poly(I,C)）的反应中，IRF信号传导略有受损，I型干扰素产生减少。最后，OPTN基因缺陷小鼠对沙门氏菌感染更易感，这在体内证实了OPTN在细菌清除中的重要性。
