Annexin A2 Regulates Autophagy in Pseudomonas aeruginosa Infection through the Akt1-mTOR-ULK1/2 Signaling Pathway.
Annexin A2 Regulates Autophagy in Pseudomonas aeruginosa Infection through the Akt1-mTOR-ULK1/2 Signaling Pathway.
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Annexin A2通过Akt1-mTOR-ULK1/2信号通路调控铜绿假单胞菌感染中的自噬作用
DOI：
10.4049/jimmunol.1500967
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发表时间：
2015-10-15
期刊：
影响因子：
--
通讯作者：
Wu M
中科院分区：
文献类型：
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作者：
Li R;Tan S;Yu M;Jundt MC;Zhang S;Wu M
早期研究报道细胞膜蛋白膜联蛋白A2 （AnxA2）在癌症的发生、侵袭和转移中发挥多种作用。最近的研究表明，AnxA2也在抗感染的免疫中起作用，但其潜在的机制仍然难以捉摸。利用小鼠感染模型，我们现在揭示了AnxA2在宿主防御铜绿假单胞菌（Pa）中的关键作用，因为与野生型（WT）幼崽相比，AnxA2−/−小鼠表现出严重的肺损伤、全身传播和更高的死亡率。此外，anxa2−/−小鼠表现出炎症因子（TNF-α, IL-6， IL-1β和IFN-γ）升高，巨噬细胞细菌清除率降低，肺部超氧化物释放增加。我们进一步发现了AnxA2和Fam13A（家族序列相似度为13，成员A）之间意想不到的分子相互作用，激活了Rho GTPase。铜绿假单胞菌感染通过抑制Akt1和mTOR诱导自噬体形成。我们的研究结果表明，AnxA2调节自噬，从而通过Akt1-mTOR-ULK1/2信号通路促进宿主对细菌的免疫。
Earlier studies reported that a cell membrane protein Annexin A2 (AnxA2) plays multiple roles in the development, invasion and metastasis of cancer. Recent studies have demonstrated that AnxA2 also functions in immunity against infection, but the underlying mechanism remains largely elusive. Using a mouse infection model, we now reveal a crucial role of AnxA2 in host defense against Pseudomonas aeruginosa (Pa), as anxa2−/− mice manifested severe lung injury, systemic dissemination, and increased mortality compared to wild-type (WT) littermates. In addition, anxa2−/− mice exhibited elevated inflammatory cytokines (TNF-α, IL-6, IL-1β and IFN-γ), decreased bacterial clearance by macrophages, and increased superoxide release in the lung. We further identified an unexpected molecular interaction between AnxA2 and Fam13A (Family with sequence similarity 13, member A), which activated Rho GTPase. P. aeruginosa infection induced autophagosome formation by inhibiting Akt1 and mTOR. Our results indicate that AnxA2 regulates autophagy and thereby contributing to host immunity against bacteria through Akt1-mTOR-ULK1/2 signaling pathway.