ATG4B/autophagin-1 regulates intestinal homeostasis and protects mice from experimental colitis
ATG4B/autophagin-1 regulates intestinal homeostasis and protects mice from experimental colitis
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DOI：
10.4161/auto.24797
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发表时间：
2013-08-01
期刊：
影响因子：
13.3
通讯作者：
Lopez-Otin, Carlos
中科院分区：
文献类型：
--
作者：
Cabrera, Sandra;Fernandez, Alvaro F.;Lopez-Otin, Carlos
通过全基因组关联鉴定炎症性肠病（IBD）易感基因已将这种病理与自噬联系起来，自噬是一种对细胞和组织稳态至关重要的溶酶体降解途径。在这里，我们描述了自噬相关的4 B，半胱氨酸肽酶/自噬蛋白-1（ATG 4 B）作为一种重要的蛋白质在控制炎症反应在实验性结肠炎。在这种病理条件下，ATG 4 B蛋白水平的增加与自噬的诱导平行。此外，在IBD患者的结肠受影响区域中，ATG 4 B表达显著降低。一致地，atg 4 b（-/-）小鼠呈现潘氏细胞异常，以及对DSS诱导的结肠炎的易感性增加。atg 4 b缺陷小鼠表现出对细菌感染的免疫应答的促炎细胞因子和介质的显著改变，这使人联想到在克罗恩病或溃疡性结肠炎患者中发现的那些。此外，抗生素治疗和野生型小鼠的骨髓移植减少了atg 4 b（-/-）小鼠的结肠炎。总之，这些结果为自噬在肠道病理学中的重要性提供了额外的证据，并将ATG 4 B描述为炎症性结肠炎中的新型保护蛋白。最后，我们提出atg 4 b缺失小鼠是体内研究的合适模型，旨在测试与自噬缺陷相关的肠道疾病的新治疗策略。
The identification of inflammatory bowel disease (IBD) susceptibility genes by genome-wide association has linked this pathology to autophagy, a lysosomal degradation pathway that is crucial for cell and tissue homeostasis. Here, we describe autophagy-related 4B, cysteine peptidase/autophagin-1 (ATG4B) as an essential protein in the control of inflammatory response during experimental colitis. In this pathological condition, ATG4B protein levels increase in parallel with the induction of autophagy. Moreover, ATG4B expression is significantly reduced in affected areas of the colon from IBD patients. Consistently, atg4b(-/-) mice present Paneth cell abnormalities, as well as an increased susceptibility to DSS-induced colitis. atg4b-deficient mice exhibit significant alterations in proinflammatory cytokines and mediators of the immune response to bacterial infections, which are reminiscent of those found in patients with Crohn disease or ulcerative colitis. Additionally, antibiotic treatments and bone marrow transplantation from wild-type mice reduced colitis in atg4b(-/-) mice. Taken together, these results provided additional evidence for the importance of autophagy in intestinal pathologies and describe ATG4B as a novel protective protein in inflammatory colitis. Finally, we propose that atg4b-null mice are a suitable model for in vivo studies aimed at testing new therapeutic strategies for intestinal diseases associated with autophagy deficiency.