Imamura Takuji, Asada Minoru, Vogt Sherri K, Rudnick David A, Lowe Mark E, Muglia Louis J
Department of Pediatrics, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis, Missouri 63110, USA.
J Biol Chem. 2002 Dec 27;277(52):50725-33. doi: 10.1074/jbc.M204159200. Epub 2002 Oct 24.
Pancreatitis is a common disease with substantial morbidity and mortality. To better understand the mechanisms conferring sensitivity or resistance to pancreatitis, we have initiated the analysis of novel acinar cell proteins. Integral membrane-associated protein-1 (Itmap1) is a CUB (complement subcomponents C1r/C1s, sea urchin Uegf protein, bone morphogenetic protein-1) and zona pellucida (ZP) domain-containing protein we find prominently expressed in pancreatic acinar cells. Within the acinar cell, Itmap1 localizes to zymogen granule membranes. Although roles in epithelial polarity, granule assembly, and mucosal protection have been postulated for CUB/ZP proteins, in vivo functions for these molecules have not been proven. To determine the function of Itmap1, we generated Itmap1-deficient mice. Itmap1(-/-) mice demonstrate increased severity of secretagogue- and diet-induced pancreatitis in comparison to Itmap1(+/+) mice. In contrast to previous animal models exhibiting altered severity of pancreatitis, Itmap1 deficiency results in impaired activation of trypsin, an enzyme believed critical for initiating a cascade of digestive zymogen activation during pancreatitis. Itmap1 deficiency does not alter zymogen granule size, appearance, or the composition of zymogen granule contents. Our results demonstrate that Itmap1 plays an essential role in trypsinogen activation and that both impaired and augmented trypsinogen activation can be associated with increased severity of pancreatitis.
胰腺炎是一种常见疾病，具有较高的发病率和死亡率。为了更好地理解导致对胰腺炎敏感或耐受的机制，我们已开始对新发现的腺泡细胞蛋白进行分析。整合膜相关蛋白1（Itmap1）是一种含CUB（补体亚成分C1r/C1s、海胆Uegf蛋白、骨形态发生蛋白1）和透明带（ZP）结构域的蛋白，我们发现它在胰腺腺泡细胞中显著表达。在腺泡细胞内，Itmap1定位于酶原颗粒膜。尽管已推测CUB/ZP蛋白在上皮极性、颗粒组装和黏膜保护中发挥作用，但这些分子的体内功能尚未得到证实。为了确定Itmap1的功能，我们培育了Itmap1基因敲除小鼠。与Itmap1(+/+)小鼠相比，Itmap1(-/-)小鼠在促分泌剂和饮食诱导的胰腺炎中表现出更严重的病情。与之前表现出胰腺炎严重程度改变的动物模型不同，Itmap1缺陷导致胰蛋白酶激活受损，胰蛋白酶是一种被认为在胰腺炎期间启动消化酶原激活级联反应中起关键作用的酶。Itmap1缺陷不会改变酶原颗粒的大小、外观或酶原颗粒内容物的组成。我们的结果表明，Itmap1在胰蛋白酶原激活中起重要作用，胰蛋白酶原激活受损和增强都可能与胰腺炎严重程度增加有关。
