Risk1, a Phosphatidylinositol 3-Kinase Effector, Promotes Rickettsia typhi Intracellular Survival.
Risk1, a Phosphatidylinositol 3-Kinase Effector, Promotes Rickettsia typhi Intracellular Survival.
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Risk1 是一种磷脂酰肌醇 3 激酶效应器，可促进伤寒立克次体细胞内存活。
作者：
Voss,OliverH;Gillespie,JosephJ;Lehman,StephanieS;Rennoll,SherriA;Beier-Sexton,Magda;Rahman,MSayeedur;Azad,AbduF
为了建立一个可居住的细胞内生态位，各种致病菌分泌的效应靶细胞内运输和调节磷酸肌肽（PI）的代谢。鼠斑疹伤寒是由专性细胞内细菌立克次体引起的，仍然是人类的一种严重疾病。然而，斑疹伤寒效应分子通过诱导吞噬作用和随后的吞噬体逃逸到细胞质中以促进细菌胞内生长的机制仍然不清楚。在这里，我们描述了一个新的分子，Risk1，作为磷脂酰肌醇3-激酶（PI3K）分泌效应物和第一个具有I类和III类PI3K活性的细菌分泌激酶。Risk1 PI3K活性的失活降低了宿主体内磷脂酰肌醇4,5-二磷酸磷酸化为磷脂酰肌醇3,4,5-三磷酸，从而减少了斑伤寒致病菌在宿主体内的定植。在感染过程中，Risk1靶向rab5 - eea1 -磷脂酰肌醇3-磷酸[PI(3)P]信号轴，促进细菌吞噬体逃逸。随后，斑疹伤寒菌发生泛素化，诱导宿主自噬；然而，自溶酶体的成熟被破坏以支持细胞内生长。有趣的是，只有酶活性的Risk1结合Beclin-1核心复合体并参与斑伤寒诱导的自噬体形成。总之，我们的数据表明，具有I类和III类PI3K双活性的Risk1改变了宿主PI代谢，从而破坏了细胞内运输，促进了伤寒杆菌的细胞内生长。大肠杆菌属是革兰氏阴性专性胞内细菌，可感染多种真核生物和脊椎动物。特别是，人体虱传的普氏立克次体和蚤传的伤寒立克次体历来困扰着人类，并继续在全球范围内重新出现。由于疫苗的缺乏和感染后期抗生素的有效性有限，致死率高达30%，因此需要更详细地阐明立克次体致病性的机制。在这里，我们描述了一种新的效应，Risk1，作为分泌的磷脂酰肌醇3-激酶（PI3K），具有独特的I类和III类双重活性。宿主定殖需要风险1，其空泡磷脂酰肌醇3-磷酸的产生调节内体运输以阻止自噬体成熟。总的来说，Risk1通过改变磷酸肌苷代谢和破坏细胞内运输来促进斑伤寒的生长。
To establish a habitable intracellular niche, various pathogenic bacteria secrete effectors that target intracellular trafficking and modulate phosphoinositide (PI) metabolism. Murine typhus, caused by the obligate intracellular bacterium Rickettsia typhi, remains a severe disease in humans. However, the mechanisms by which R. typhi effector molecules contribute to internalization by induced phagocytosis and subsequent phagosomal escape into the cytosol to facilitate the intracellular growth of the bacteria remain ill-defined. Here, we characterize a new molecule, Risk1, as a phosphatidylinositol 3-kinase (PI3K) secreted effector and the first bacterial secretory kinase with both class I and III PI3K activities. Inactivation of Risk1 PI3K activities reduced the phosphorylation of phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-trisphosphate within the host, which consequently diminished host colonization by R. typhi. During infection, Risk1 targets the Rab5-EEA1-phosphatidylinositol 3-phosphate [PI(3)P] signaling axis to promote bacterial phagosomal escape. Subsequently, R. typhi undergoes ubiquitination and induces host autophagy; however, maturation to autolysosomes is subverted to support intracellular growth. Intriguingly, only enzymatically active Risk1 binds the Beclin-1 core complex and contributes to R. typhi-induced autophagosome formation. In sum, our data suggest that Risk1, with dual class I and class III PI3K activities, alters host PI metabolism and consequently subverts intracellular trafficking to facilitate intracellular growth of R. typhi.IMPORTANCERickettsiaspecies are Gram-negative obligate intracellular bacteria that infect a wide range of eukaryotes and vertebrates. In particular, human body louse-borne Rickettsia prowazekii and flea-borne Rickettsia typhi have historically plagued humankind and continue to reemerge globally. The unavailability of vaccines and limited effectiveness of antibiotics late in infection place lethality rates up to 30%, highlighting the need to elucidate the mechanisms ofRickettsiapathogenicity in greater detail. Here, we characterize a new effector, Risk1, as a secreted phosphatidylinositol 3-kinase (PI3K) with unique dual class I and class III activities. Risk1 is required for host colonization, and its vacuolar phosphatidylinositol 3-phosphate generation modulates endosomal trafficking to arrest autophagosomal maturation. Collectively, Risk1 facilitates R. typhi growth by altering phosphoinositide metabolism and subverting intracellular trafficking.