Chlamydia trachomatis co-opts GBF1 and CERT to acquire host sphingomyelin for distinct roles during intracellular development.
Chlamydia trachomatis co-opts GBF1 and CERT to acquire host sphingomyelin for distinct roles during intracellular development.
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DOI：
10.1371/journal.ppat.1002198
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发表时间：
2011-09
期刊：
影响因子：
6.7
通讯作者：
Engel JN
中科院分区：
文献类型：
--
作者：
Elwell CA;Jiang S;Kim JH;Lee A;Wittmann T;Hanada K;Melancon P;Engel JN
专性细胞内病原体沙眼衣原体在获得宿主鞘磷脂（SM）的膜结合包涵体内复制，这是复制以及包涵体生物合成所必需的过程。先前的研究表明，SM是通过Brefeldin A（BFA）敏感的囊泡运输途径获得的，尽管矛盾的是，该途径不适合细菌复制。这一发现表明，其他脂质转运机制参与收购的主机SM。在这项工作中，我们询问的作用，BFA敏感和BFA不敏感的脂质运输途径的特定组件，以确定其在感染过程中的SM收购的贡献。我们发现C.沙眼衣原体劫持囊泡和非囊泡脂质运输途径的组分以获得SM，但从这些单独途径获得的SM被病原体以不同的方式利用。我们证明了C.沙眼衣原体选择性地仅选择三种已知BFA靶标之一，GBF 1，其是囊泡介导的SM获得的早期分泌途径内Arf 1依赖性囊泡运输的调节剂。Arf 1/GBF 1依赖的SM获取途径对于包涵体膜的生长和稳定性是必不可少的，但不是细菌复制所必需的。与此相反，我们表明，C。沙眼衣原体选择CERT，一种脂质转移蛋白，它是非囊泡ER向高尔基体运输神经酰胺（SM的前体）的关键组分，C.沙眼复制我们证明了C.沙眼衣原体将CERT、其ER结合伴侣VAP-A和SM降解酶SMS 1和SMS 2招募到包涵体中，并提出这些蛋白质在包涵体处或附近建立了一个现场SM生物合成工厂。我们推测，通过CERT依赖性神经酰胺转运获得SM并随后转化为SM是C。通过GBF 1依赖性途径获得的SM对包涵体的生长和稳定性至关重要。我们的研究结果揭示了一种新的机制，细胞内的病原体重定向SM生物合成到其复制生态位。 C.沙眼是发展中国家非先天性失明的主要原因，也是西方国家性传播疾病和非先天性不育的头号原因。衣原体感染能够导致不育和失明，与慢性疾病有关，这些感染的异常流行和种类使其成为公众关注的首要问题。这种病原体必须建立一个保护性的膜结合的生态位，并在感染过程中从宿主细胞获得必需的脂质，以便生存和复制。这项研究确定了新的机制，C。沙眼衣原体劫持各种脂质运输蛋白在细胞内发育过程中的不同作用。这些脂质运输途径的破坏导致其保护性生态位的生长和稳定性的改变以及复制缺陷。了解这些宿主-病原体相互作用的分子机制将为开发新的治疗，诊断和预防策略带来合理的方法。
The obligate intracellular pathogen Chlamydia trachomatis replicates within a membrane-bound inclusion that acquires host sphingomyelin (SM), a process that is essential for replication as well as inclusion biogenesis. Previous studies demonstrate that SM is acquired by a Brefeldin A (BFA)-sensitive vesicular trafficking pathway, although paradoxically, this pathway is dispensable for bacterial replication. This finding suggests that other lipid transport mechanisms are involved in the acquisition of host SM. In this work, we interrogated the role of specific components of BFA-sensitive and BFA-insensitive lipid trafficking pathways to define their contribution in SM acquisition during infection. We found that C. trachomatis hijacks components of both vesicular and non-vesicular lipid trafficking pathways for SM acquisition but that the SM obtained from these separate pathways is being utilized by the pathogen in different ways. We show that C. trachomatis selectively co-opts only one of the three known BFA targets, GBF1, a regulator of Arf1-dependent vesicular trafficking within the early secretory pathway for vesicle-mediated SM acquisition. The Arf1/GBF1-dependent pathway of SM acquisition is essential for inclusion membrane growth and stability but is not required for bacterial replication. In contrast, we show that C. trachomatis co-opts CERT, a lipid transfer protein that is a key component in non-vesicular ER to trans-Golgi trafficking of ceramide (the precursor for SM), for C. trachomatis replication. We demonstrate that C. trachomatis recruits CERT, its ER binding partner, VAP-A, and SM synthases, SMS1 and SMS2, to the inclusion and propose that these proteins establish an on-site SM biosynthetic factory at or near the inclusion. We hypothesize that SM acquired by CERT-dependent transport of ceramide and subsequent conversion to SM is necessary for C. trachomatis replication whereas SM acquired by the GBF1-dependent pathway is essential for inclusion growth and stability. Our results reveal a novel mechanism by which an intracellular pathogen redirects SM biosynthesis to its replicative niche. C. trachomatis is the leading cause of non-congenital blindness in developing countries and is the number one cause of sexually transmitted disease and non-congenital infertility in Western countries. The capacity of Chlamydia infections to lead to infertility and blindness, their association with chronic diseases, and the extraordinary prevalence and array of these infections make them public concerns of primary importance. This pathogen must establish a protective membrane-bound niche and acquire essential lipids from the host cell during infection in order to survive and replicate. This study identifies novel mechanisms by which C. trachomatis hijacks various lipid trafficking proteins for distinct roles during intracellular development. Disruption of these lipid trafficking pathways results in alterations in the growth and stability of its protective niche as well as a defect in replication. Understanding the molecular mechanisms of these host-pathogen interactions will lead to rational approaches for the development of novel therapeutics, diagnostics, and preventative strategies.
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DOI：
10.1111/j.1600-0854.2008.00810.x
发表时间：
2008-11
期刊：
Traffic (Copenhagen, Denmark)
影响因子：
--
作者：
Chandran S;Machamer CE
通讯作者：
Machamer CE
影响因子：
64.8
作者：
Guo, Yi;Walther, Tobias C.;Farese, Robert V., Jr.
通讯作者：
Farese, Robert V., Jr.
影响因子：
4
作者：
Dumaresq-Doiron, Karine;Savard, Marie-France;Lefrancois, Stephane
通讯作者：
Lefrancois, Stephane
DOI：
10.1073/pnas.92.11.4877
发表时间：
1995-05-23
影响因子：
11.1
作者：
HACKSTADT, T;SCIDMORE, MA;ROCKEY, DD
通讯作者：
ROCKEY, DD
影响因子：
6.7
作者：
Elwell, Cherilyn A.;Ceesay, Alhaji;Kim, Jung Hwa;Kalman, Daniel;Engel, Joanne N.
通讯作者：
Engel, Joanne N.