Malaria parasite evades mosquito immunity by glutaminyl cyclase-mediated posttranslational protein modification.
Malaria parasite evades mosquito immunity by glutaminyl cyclase-mediated posttranslational protein modification.
复制标题
DOI：
10.1073/pnas.2209729119
复制
发表时间：
2022-08-30
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
谷氨酰环酶(QC)对一些蛋白质进行化学修饰，调节人类的重要过程，包括恶性细胞的免疫逃避。我们发现，在蚊子体内发育的疟疾寄生虫阶段，一种QC酶也是活跃的。缺乏QC活性的突变寄生虫在从中肠转移到唾液腺时被包裹起来消除。破坏蚊子的包囊反应使寄生虫得以存活，这表明QC介导的修饰阻止了免疫识别。我们提供的直接证据表明，QC对疟疾寄生虫主要表面蛋白的特定修饰对于生存是重要的。了解疟疾寄生虫是如何逃避蚊子免疫的，可能会为设计新的战略来阻断疟疾传播打开可能性。谷氨酰胺环化酶(QC)将靶蛋白的N-末端谷氨酰胺或谷氨酸残基修饰为环状焦谷氨酸(PGlu)。在这里，我们报告了疟原虫QC的生化和功能分析。我们发现，啮齿动物和人类疟疾寄生虫的qc缺失突变体的子孢子可以被蚊子免疫系统识别，并在到达血腔时变黑。对啮齿动物疟疾qc缺失突变体的详细分析表明，感染qc缺失突变或qc催化死亡突变的蚊子唾液腺中的子孢子数量减少。这种表型可以通过基因互补或通过破坏蚊子的黑化或血细胞吞噬来挽救。伯氏疟原虫主要子孢子表面蛋白(环子孢子蛋白；CSP)的单一QC靶标谷氨酰胺突变也会导致子孢子黑化。这些发现表明，QC介导的表面蛋白的翻译后修饰是蚊子免疫系统逃避杀灭子孢子的基础。
Chemical modification of some proteins by the enzyme glutaminyl cyclase (QC) modulates important processes in humans, including immune evasion by malignant cells. We found that a QC enzyme is also active in malaria parasite stages developing in the mosquito. Mutant parasites that lack QC activity are eliminated by encapsulation as they transit from the midgut to the salivary glands. Disrupting the mosquito encapsulation response allows parasites to survive, indicating that QC-mediated modifications prevent immune recognition. We provide direct evidence that a specific modification of a major surface protein of the malaria parasite by QC is important for survival. Understanding how malaria parasites evade mosquito immunity could open the possibility to designing novel strategies to disrupt malaria transmission. Glutaminyl cyclase (QC) modifies N-terminal glutamine or glutamic acid residues of target proteins into cyclic pyroglutamic acid (pGlu). Here, we report the biochemical and functional analysis of Plasmodium QC. We show that sporozoites of QC-null mutants of rodent and human malaria parasites are recognized by the mosquito immune system and melanized when they reach the hemocoel. Detailed analyses of rodent malaria QC-null mutants showed that sporozoite numbers in salivary glands are reduced in mosquitoes infected with QC-null or QC catalytically dead mutants. This phenotype can be rescued by genetic complementation or by disrupting mosquito melanization or phagocytosis by hemocytes. Mutation of a single QC-target glutamine of the major sporozoite surface protein (circumsporozoite protein; CSP) of the rodent parasite Plasmodium berghei also results in melanization of sporozoites. These findings indicate that QC-mediated posttranslational modification of surface proteins underlies evasion of killing of sporozoites by the mosquito immune system.
登录
查看更多内容
影响因子：
5.3
作者：
Clayton AM;Dong Y;Dimopoulos G
通讯作者：
Dimopoulos G
影响因子：
3.6
作者：
Lin, Jing-wen;Meireles, Patricia;Khan, Shahid M.
通讯作者：
Khan, Shahid M.
影响因子：
5.4
作者：
Booth RE;Lovell SC;Misquitta SA;Bateman RC Jr
通讯作者：
Bateman RC Jr
DOI：
10.1073/pnas.79.18.5651
发表时间：
1982-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
COCHRANE, AH;SANTORO, F;NUSSENZWEIG, RS
通讯作者：
NUSSENZWEIG, RS
影响因子：
3
作者：
Douradinha, Bruno;Augustijn, Kevin D.;Thompson, Joanne
通讯作者：
Thompson, Joanne