Dataset Information

Akt/AS160 Signaling Pathway Inhibition Impairs Infection by Decreasing Rab14-Controlled Sphingolipids Delivery to Chlamydial Inclusions.

ABSTRACT: Chlamydia trachomatis, an obligate intracellular bacterium, intercepts different trafficking pathways of the host cell to acquire essential lipids for its survival and replication, particularly from the Golgi apparatus via a Rab14-mediated transport. Molecular mechanisms underlying how these bacteria manipulate intracellular transport are a matter of intense study. Here, we show that C. trachomatis utilizes Akt/AS160 signaling pathway to promote sphingolipids delivery to the chlamydial inclusion through Rab14-controlled vesicular transport. C. trachomatis provokes Akt phosphorylation along its entire developmental life cycle and recruits phosphorylated Akt (pAkt) to the inclusion membrane. As a consequence, Akt Substrate of 160 kDa (AS160), also known as TBC1D4, a GTPase Activating Protein (GAP) for Rab14, is phosphorylated and therefore inactivated. Phosphorylated AS160 (pAS160) loses its ability to promote GTP hydrolysis, favoring Rab14 binding to GTP. Akt inhibition by an allosteric isoform-specific Akt inhibitor (iAkt) prevents AS160 phosphorylation and reduces Rab14 recruitment to chlamydial inclusions. iAkt further impairs sphingolipids acquisition by C. trachomatis-inclusion and provokes lipid retention at the Golgi apparatus. Consequently, treatment with iAkt decreases chlamydial inclusion size, bacterial multiplication, and infectivity in a dose-dependent manner. Similar results were found in AS160-depleted cells. By electron microscopy, we observed that iAkt generates abnormal bacterial forms as those reported after sphingolipids deprivation or Rab14 silencing. Taken together, our findings indicate that targeting the Akt/AS160/Rab14 axis could constitute a novel strategy to limit chlamydial infections, mainly for those caused by antibiotic-resistant bacteria.

SUBMITTER: Capmany A

PROVIDER: S-EPMC6456686 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Akt/AS160 Signaling Pathway Inhibition Impairs Infection by Decreasing Rab14-Controlled Sphingolipids Delivery to Chlamydial Inclusions.

Capmany Anahí A Gambarte Tudela Julián J Alonso Bivou Mariano M Damiani María T MT

Frontiers in microbiology 20190403

<i>Chlamydia trachomatis</i>, an obligate intracellular bacterium, intercepts different trafficking pathways of the host cell to acquire essential lipids for its survival and replication, particularly from the Golgi apparatus via a Rab14-mediated transport. Molecular mechanisms underlying how these bacteria manipulate intracellular transport are a matter of intense study. Here, we show that <i>C. trachomatis</i> utilizes Akt/AS160 signaling pathway to promote sphingolipids delivery to the chlamy ...[more]

PMID: 31001235

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Project description:Bladder cancer (BLCA) is the 9th most common cancer of mortality. Autophagy and epithelial to mesenchymal transition (EMT) have an essential role in cancer invasion and metastasis. However, the relationship between autophagy and EMT is still poorly understood in BLCA. Functional enrichment and pathway network analysis were carried out. Comprehensive protein-protein interactions (PPI) networks were proposed to prioritize candidate autophagy-related genes. Furthermore, an autophagy-related signature and a nomogram model were established by integrating clinical information and this signature risk score to evaluate candidate autophagy-related genes. RAB14 expression and its association with pathological information and survival were evaluated in samples from TCGA dataset. Knocking down RAB14 in T24 cells was constructed, and immunofluorescence staining, transmission electron microscopy, immunohistochemistry and western blotting and a series of functional assays were performed to evaluate the migration, invasion, EMT and autophagy abilities of BLCA cells. The autophagy-related gene RAB14 was the only candidate gene identified by three kinds of analytic approaches. RAB14 was highly upregulated in BLCA and correlated with clinical outcomes based on TCGA BLCA datasets. Knocking down RAB14 was found to inhibit EMT and autophagy in T24 cells. RAB14 levels were positively related to those of LC3B and Beclin1, two genes with critical roles in the autophagy process, and the correlation was further confirmed in clinical tissue specimens by IHC and western blot analysis. In addition, RAB14-promoted EMT, migration, and invasion in T24 cells could be partially reversed by autophagy activator, rapamycin. The effects of RAB14 on autophagy was associated with level of p-Akt, indicating that they were possibly mediated via PI3K/AKT signaling. These findings indicated that autophagy-related gene RAB14-promoted EMT, migration and invasion of bladder cancer via the Akt-associated autophagic pathway.

Dataset Information

Akt/AS160 Signaling Pathway Inhibition Impairs Infection by Decreasing Rab14-Controlled Sphingolipids Delivery to Chlamydial Inclusions.

Publications

Akt/AS160 Signaling Pathway Inhibition Impairs Infection by Decreasing Rab14-Controlled Sphingolipids Delivery to Chlamydial Inclusions.

Similar Datasets

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