Altered posttranslational processing of glycoproteins in cerulein-induced pancreatitis.
Altered posttranslational processing of glycoproteins in cerulein-induced pancreatitis.
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DOI：
10.1016/j.yexcr.2005.04.003
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发表时间：
2005-08
影响因子：
3.7
通讯作者：
R. Lisle
中科院分区：
文献类型：
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作者：
R. Lisle
急性胰腺炎是一种引起炎症的自身消化系统疾病。在细胞水平，急性胰腺炎破坏了分泌途径中的翻译后蛋白质加工和运输，并且酶原在腺泡细胞中被激活。为了更好地理解胰腺炎分泌途径的破坏，脉冲追踪[35 S]met/cys分析用于研究超大雨蛙肽刺激对小鼠胰腺主要硫酸化糖蛋白、前Muclin和溶酶体膜蛋白LAMP 1的分泌途径中的翻译后修饰的影响。最大雨蛙肽或高浓度蛙皮素刺激对糖蛋白加工几乎没有影响。相比之下，超大雨蛙肽刺激强烈抑制前Muclin加工，如通过Muclin未能达到其正常成熟大小300 kDa并变得高度硫酸化和降低前Muclin的蛋白水解裂解以产生apactin所测量的。用内切糖苷酶H消化免疫沉淀的[35 S]met/cys标记的Muclin和LAMP 1表明，在内侧高尔基体室之前发生了最大的雨蛙肽诱导的加工阻滞。在超大雨蛙肽刺激下，形成含有Muclin、淀粉酶和LAMP 1的空泡。早期的放射自显影研究表明，新合成的蛋白质最终出现在胰腺炎相关的空泡中，因此翻译后加工不完全的糖蛋白很可能也存在于空泡中。由于糖蛋白被认为可以保护溶酶体和酶原颗粒的膜，当它们没有被正确加工时，它们的防御机制可能会受损，这可能会导致胰腺炎中的空泡脆性。
Acute pancreatitis is an auto-digestive disease resulting in inflammation. At the cellular level, acute pancreatitis disrupts posttranslational protein processing and traffic in the secretory pathway, and zymogens become activated in the acinar cell. To better understand the disruption of the secretory pathway in pancreatitis, pulse-chase [35S]met/cys analysis was used to study the effects of supramaximal cerulein stimulation on posttranslational modification in the secretory pathway of the major sulfated glycoprotein of the mouse pancreas, pro-Muclin, and the lysosomal membrane protein LAMP1. Maximal cerulein or high concentration bombesin stimulation had little effect on glycoprotein processing. By contrast, supramaximal cerulein stimulation strongly inhibited pro-Muclin processing as measured by the failure of Muclin to attain its normal mature size of 300 kDa and to become highly sulfated and decreased proteolytic cleavage of pro-Muclin to produce apactin. Digestion of immunoprecipitated [35S]met/cys-labeled Muclin and LAMP1 with endoglycosidase H demonstrated that the supramaximal cerulein-induced block in processing occurred before the medial Golgi compartment. With supramaximal cerulein stimulation, vacuoles formed which contained Muclin, amylase, and LAMP1. Earlier autoradiographic studies showed that newly synthesized proteins end up in pancreatitis-associated vacuoles, so it is likely that glycoproteins with incomplete posttranslational processing are also present in vacuoles. Because glycoproteins are believed to protect the membranes of lysosomes and zymogen granules, when they are not correctly processed, their defensive mechanisms may be impaired, and this could contribute to vacuole fragility in pancreatitis.