Zranb1-mutant mice display abnormal colonic mucus production and exacerbation of DSS-induced colitis.
Zranb1-mutant mice display abnormal colonic mucus production and exacerbation of DSS-induced colitis.
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DOI：
10.1016/j.bbrc.2022.08.046
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发表时间：
2022-08
影响因子：
3.1
通讯作者：
Akiko Tamura;Go Ito;Hiroki Matsuda;Yoichi Nibe-Shirakihara;Y. Hiraoka;Sayuki Kitagawa;Yui Hiraguri-Yui-Hira
中科院分区：
文献类型：
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作者：
Akiko Tamura;Go Ito;Hiroki Matsuda;Yoichi Nibe-Shirakihara;Y. Hiraoka;Sayuki Kitagawa;Yui Hiraguri-Yui-Hira
粘蛋白MUC 2是结肠粘液层的一种组分，其表达在肠内稳态中起着至关重要的作用。在这里，我们描述了一种新的MUC 2表达调节剂，去泛素化酶ZRANB 1（Trabid）。在氨基酸位置443处将半胱氨酸改变为丝氨酸的ZRANB 1突变影响泛素化。为了分析ZRANB 1在肠道中的功能，我们使用CRISPR/Cas9系统产生了Zranb 1C 443 S突变敲入（Zranb 1C 443 S/C443 S）小鼠。来自Zranb 1C 443 S/C443 S小鼠的结肠类器官在分化为杯状细胞后显示Muc 2 mRNA表达降低。最后，我们分析了葡聚糖硫酸钠诱导的结肠炎，以了解ZRANB 1在肠道炎症中的作用。患有结肠炎的Zranb 1C 443 S/C443 S小鼠表现出显著的体重减轻，结肠长度减少，临床和病理评分恶化，表明ZRANB 1有助于肠道稳态。总之，这些结果表明，ZRANB 1调节MUC 2表达和肠道炎症，这可能有助于阐明炎症性肠病的发病机制，并开发针对ZRANB 1的新疗法。
Expression of mucin MUC2, a component of the colonic mucus layer, plays a crucial role in intestinal homeostasis. Here, we describe a new regulator of MUC2 expression, the deubiquitinase ZRANB1 (Trabid). A ZRANB1 mutation changing cysteine to serine in amino acid position 443, affects ubiquitination. To analyze ZRANB1 function in the intestine, we generatedZranb1C443S mutant knock-in (Zranb1C443S/C443S) mice using the CRISPR/Cas9 system.Zranb1C443S/C443Smice exhibited decreased mRNA expression and MUC2 production. Colonic organoids fromZranb1C443S/C443Smice displayed decreasedMuc2mRNA expression following differentiation into goblet cells. Finally, we analyzed dextran sulfate sodium-induced colitis to understand ZRANB1's role in intestinal inflammation.Zranb1C443S/C443Smice with colitis exhibited significant weight loss, reduced colon length, and worsening clinical and pathological scores, indicating that ZRANB1 contributes to intestinal homeostasis. Together, these results suggest that ZRANB1 regulates MUC2 expression and intestinal inflammation, which may help elucidating the pathogenesis of inflammatory bowel disease and developing new therapeutics targeting ZRANB1.