Progranulin Controls Sepsis via C/EBPα-Regulated Il10 Transcription and Ubiquitin Ligase/Proteasome-Mediated Protein Degradation.
Progranulin Controls Sepsis via C/EBPα-Regulated Il10 Transcription and Ubiquitin Ligase/Proteasome-Mediated Protein Degradation.
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颗粒体蛋白前体通过 C/EBPalpha 调节的 Il10 转录和泛素连接酶/蛋白酶体介导的蛋白质降解控制脓毒症
DOI：
10.4049/jimmunol.1600862
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发表时间：
2016-10-15
期刊：
影响因子：
--
通讯作者：
Ma X
中科院分区：
文献类型：
--
作者：
Yan W;Ding A;Kim HJ;Zheng H;Wei F;Ma X
原颗粒蛋白(PGRN)是一种广泛表达的多效性蛋白质，参与细胞增殖、神经元发育和伤口愈合等多种生物学过程。然而，PGRN在病原体诱导的全身炎症中的调节作用和涉及的机制尚不清楚。在这里，我们显示了在多菌败血症和内毒素血症模型中，PGRN缺陷小鼠的死亡率增加，组织炎性细胞因子水平增加，IL-10产生减少。相反，给予重组PGRN可降低PGRN缺陷小鼠对内毒素休克的易感性，并以TNFR依赖的方式增加内毒素激活的巨噬细胞产生IL-10。分子分析表明，转录因子CCAAT/增强子结合蛋白α在PGRN调节的IL-10表达中起直接作用。C/eBPα缺陷的巨噬细胞产生较少的IL-10以响应内毒素。此外，造血细胞中C/EBPα缺陷的小鼠非常容易受到内毒素诱导的感染性休克的影响。最后，pGRN缺陷细胞产生IL-10的主要原因是通过E3泛素结合酶E6AP和蛋白酶体介导的降解降低了C/eBPα蛋白的稳定性。本研究首次证明PGRN通过调节C/EBPα、IL-10和泛素-蛋白酶体蛋白分解途径的水平和活性，是全身炎症的非冗余调节因子。这些结果对PGRN功能不全及其突变相关的全身性和器官特异性炎症性人类疾病具有强烈而深刻的影响。
Progranulin (PGRN) is a widely expressed, pleiotropic protein that is involved in diverse biological processes including cellular proliferation, neuron development and wound healing. However, the role of PGRN in the regulation of pathogen-induced systemic inflammation and the mechanisms involved have not been established. Here we show that PGRN-deficient mice display heightened mortality in models of polymicrobial sepsis and endotoxinemia, with increased tissue levels of inflammatory cytokines and reduced IL-10 production. Conversely, administration of recombinant PGRN decreases the susceptibility of PGRN-deficient mice to LPS-induced endotoxemic shock and augments IL-10 production by LPS-activated macrophages in a TNFR-dependent manner. Molecular analysis reveals a direct role of the transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα) in PGRN-regulated IL-10 expression. C/EBPα–deficient macrophages produce less IL-10 in response to LPS. Further, mice deficient in C/EBPα in hematopoietic cells are highly vulnerable to LPS-induced septic shock. Lastly, the defective IL-10 production by PGRN-deficient cells is primarily due to reduced C/EBPα protein stability via the E3 ubiquitin conjugating enzyme E6AP and proteasome-mediated degradation. This study provides the first evidence that PGRN is a non-redundant regulator of systemic inflammation via modulating the levels and activity of C/EBPα, IL-10 and the ubiquitin-proteasome proteolysis pathway. The results bear strong and profound implications for PGRN-insufficiency and its mutation-associated systemic and organ-specific inflammatory human diseases.
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影响因子：
4
作者：
Bateman, Andrew;Bennett, Hugh P. J.
通讯作者：
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