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首页> 外文期刊>Cellular Physiology and Biochemistry >Schlafen 12 Interaction with SerpinB12 and Deubiquitylases Drives Human Enterocyte Differentiation
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Schlafen 12 Interaction with SerpinB12 and Deubiquitylases Drives Human Enterocyte Differentiation

机译：Schlafen 12与SerpinB12和去泛素化酶的相互作用驱动人类肠上皮细胞分化。

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Background/Aims Human enterocytic differentiation is altered during development, fasting, adaptation, and bariatric surgery, but its intracellular control remains unclear. We hypothesized that Schlafen 12 (SLFN12) regulates enterocyte differentiation. Methods We used laser capture dissection of epithelium, qRT-PCR, and immunohistochemistry to evaluate SLFN12 expression in biopsies of control and fasting human duodenal mucosa, and viral overexpression and siRNA to trace the SLFN12 pathway in human Caco-2 and HIEC6 intestinal epithelial cells. Results Fasting human duodenal mucosa expressed less SLFN12 mRNA and protein, accompanied by decreases in enterocytic markers like sucrase-isomaltase. SLFN12 overexpression increased Caco-2 sucrase-isomaltase promoter activity, mRNA, and protein independently of proliferation, and activated the SLFN12 putative promoter. SLFN12 coprecipitated Serpin B12 (SERPB12). An inactivating SLFN12 point mutation prevented both SERPB12 binding and sucrase-isomaltase induction. SERPB12 overexpression also induced sucrase-isomaltase, while reducing SERPB12 prevented the SLFN12 effect on sucrase-isomaltase. Sucrase-isomaltase induction by both SLFN12 and SERPB12 was attenuated by reducing UCHL5 or USP14, and blocked by reducing both. SERPB12 stimulated USP14 but not UCHL5 activity. SERPB12 coprecipitated USP14 but not UCHL5. Moreover, SLFN12 increased protein levels of the sucrase-isomaltase-promoter-binding transcription factor cdx2 without altering Cdx2 mRNA. This was prevented by reducing UCHL5 and USP14. We further validated this pathway in vitro and in vivo. SLFN12 or SERPB12 overexpression induced sucrase-isomaltase in human non-malignant HIEC-6 enterocytes. Conclusions SLFN12 regulates human enterocytic differentiation by a pathway involving SERPB12, the deubiquitylases, and Cdx2. This pathway may be targeted to manipulate human enterocytic differentiation in mucosal atrophy, short gut or obesity.
机译：背景/目的人类的肠细胞分化在发育，禁食，适应和减肥手术过程中会改变，但其细胞内控制仍不清楚。我们假设Schlafen 12（SLFN12）调节肠细胞分化。方法我们使用激光捕获上皮解剖，qRT-PCR和免疫组化方法评估对照和空腹人十二指肠粘膜活检中SLFN12的表达，并通过病毒过表达和siRNA追踪人Caco-2和HIEC6肠上皮细胞的SLFN12途径。结果空腹的人十二指肠粘膜表达较少的SLFN12 mRNA和蛋白，并伴随着蔗糖酶-异麦芽糖酶等肠细胞标志物的减少。 SLFN12的过表达增加了Caco-2蔗糖酶-异麦芽糖酶启动子的活性，mRNA和蛋白质，而与增殖无关，并激活了SLFN12的假定启动子。 SLFN12共沉淀Serpin B12（SERPB12）。失活的SLFN12点突变阻止了SERPB12结合和蔗糖酶-异麦芽糖酶的诱导。 SERPB12的过表达也诱导了蔗糖酶-异麦芽糖酶，而降低SERPB12阻止了SLFN12对蔗糖酶-异麦芽糖酶的作用。通过减少UCHL5或USP14可以减弱SLFN12和SERPB12的蔗糖异麦芽糖酶诱导，并通过减少两者来阻止。 SERPB12刺激USP14，但不刺激UCHL5活性。 SERPB12共沉淀USP14，但不沉淀UCHL5。此外，SLFN12在不改变Cdx2 mRNA的情况下增加了蔗糖酶-异麦芽糖酶-启动子结合转录因子cdx2的蛋白质水平。通过减少UCHL5和USP14可以防止这种情况。我们进一步在体外和体内验证了该途径。 SLFN12或SERPB12过表达诱导人非恶性HIEC-6肠上皮细胞蔗糖酶-异麦芽糖酶。结论SLFN12通过涉及SERPB12，去泛素化酶和Cdx2的途径调节人的肠细胞分化。该途径可被靶向以操纵人在粘膜萎缩，短肠或肥胖中的肠细胞分化。

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