Cornick Steve, Moreau France, Chadee Kris
Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
PLoS Pathog. 2016 Apr 13;12(4):e1005579. doi: 10.1371/journal.ppat.1005579. eCollection 2016 Apr.
Critical to the pathogenesis of intestinal amebiasis, Entamoeba histolytica (Eh) induces mucus hypersecretion and degrades the colonic mucus layer at the site of invasion. The parasite component(s) responsible for hypersecretion are poorly defined, as are regulators of mucin secretion within the host. In this study, we have identified the key virulence factor in live Eh that elicits the fast release of mucin by goblets cells as cysteine protease 5 (EhCP5) whereas, modest mucus secretion occurred with secreted soluble EhCP5 and recombinant CP5. Coupling of EhCP5-αvβ3 integrin on goblet cells facilitated outside-in signaling by activating SRC family kinases (SFK) and focal adhesion kinase that resulted in the activation/phosphorlyation of PI3K at the site of Eh contact and production of PIP3. PKCδ was activated at the EhCP5-αvβ3 integrin contact site that specifically regulated mucin secretion though the trafficking vesicle marker myristoylated alanine-rich C-kinase substrate (MARCKS). This study has identified that EhCP5 coupling with goblet cell αvβ3 receptors can initiate a signal cascade involving PI3K, PKCδ and MARCKS to drive mucin secretion from goblet cells critical in disease pathogenesis.
对肠道阿米巴病发病机制至关重要的是，溶组织内阿米巴（Eh）会诱导黏液分泌过多，并在入侵部位降解结肠黏液层。导致分泌过多的寄生虫成分尚不清楚，宿主内黏蛋白分泌的调节因子也不清楚。在本研究中，我们已确定活Eh中引发杯状细胞快速释放黏蛋白的关键毒力因子为半胱氨酸蛋白酶5（EhCP5），而分泌的可溶性EhCP5和重组CP5则引起适度的黏液分泌。杯状细胞上的EhCP5-αvβ3整合素通过激活SRC家族激酶（SFK）和粘着斑激酶促进外向内信号传导，导致Eh接触部位PI3K的激活/磷酸化以及PIP3的产生。PKCδ在EhCP5-αvβ3整合素接触部位被激活，通过运输囊泡标记物肉豆蔻酰化富含丙氨酸的C激酶底物（MARCKS）特异性调节黏蛋白分泌。本研究已确定EhCP5与杯状细胞αvβ3受体的偶联可启动涉及PI3K、PKCδ和MARCKS的信号级联反应，以驱动杯状细胞分泌黏蛋白，这对疾病发病机制至关重要。
