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Gliotoxin Induces Cofilin Phosphorylation to Promote Actin Cytoskeleton Dynamics and Internalization of Aspergillus fumigatus Into Type II Human Pneumocyte Cells.

ABSTRACT: Aspergillus fumigatus is able to internalize into lung epithelial cells to escape from immune attack for further dissemination. We previously reported that gliotoxin, a major mycotoxin of A. fumigatus, promotes this internalization; however, the mechanism remained unclear. Here, we report that gliotoxin is able to induce cofilin phosphorylation in A549 type II human pneumocytes. Either too high or too low a level of cofilin phosphorylation blocked the gliotoxin-induced actin cytoskeleton rearrangement and A. fumigatus internalization. LIM domain kinase 1 (LIMK1) and its upstream small GTPases (Cdc42 and RhoA, but not Rac1) predominantly mediated the gliotoxin-induced cofilin phosphorylation and A. fumigatus internalization. Simultaneously, gliotoxin significantly stimulated an increase in cAMP; however, adding an antagonist of PKA did not block gliotoxin-induced A. fumigatus internalization. In vivo, exogenous gliotoxin helped gliotoxin synthesis deficient strain gliP? invade into the lung tissue and the lung fungal burden increased markedly in immunosuppressed mice. In conclusion, these data revealed a novel role of gliotoxin in inducing cofilin phosphorylation mostly through the Cdc42/RhoA-LIMK1 signaling pathway to promote actin cytoskeleton rearrangement and internalization of A. fumigatus into type II human pneumocytes.

SUBMITTER: Zhang C

PROVIDER: S-EPMC6591310 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Gliotoxin Induces Cofilin Phosphorylation to Promote Actin Cytoskeleton Dynamics and Internalization of Aspergillus fumigatus Into Type II Human Pneumocyte Cells.

Zhang Changjian C Chen Fangyan F Liu Xiaoyu X Han Xuelin X Hu Yingsong Y Su Xueting X Chen Yong Y Sun Yansong Y Han Li L

Frontiers in microbiology 20190618

Aspergillus fumigatus is able to internalize into lung epithelial cells to escape from immune attack for further dissemination. We previously reported that gliotoxin, a major mycotoxin of A. fumigatus, promotes this internalization; however, the mechanism remained unclear. Here, we report that gliotoxin is able to induce cofilin phosphorylation in A549 type II human pneumocytes. Either too high or too low a level of cofilin phosphorylation blocked the gliotoxin-induced actin cytosk ...[more]

PMID: 31275272

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Project description:Mechanistic studies on gliotoxin biosynthesis and self-protection in Aspergillus fumigatus, both of which require the gliotoxin oxidoreductase GliT, have revealed a rich landscape of highly novel biochemistries, yet key aspects of this complex molecular architecture remain obscure. Here we show that an A. fumigatus ΔgliA strain is completely deficient in gliotoxin secretion but still retains the ability to efflux bisdethiobis(methylthio)gliotoxin (BmGT). This correlates with a significant increase in sensitivity to exogenous gliotoxin because gliotoxin trapped inside the cell leads to (i) activation of the gli cluster, as disabling gli cluster activation, via gliZ deletion, attenuates the sensitivity of an A. fumigatus ΔgliT strain to gliotoxin, thus implicating cluster activation as a factor in gliotoxin sensitivity, and (ii) increased methylation activity due to excess substrate (dithiol gliotoxin) for the gliotoxin bis-thiomethyltransferase GtmA. Intracellular dithiol gliotoxin is oxidized by GliT and subsequently effluxed by GliA. In the absence of GliA, gliotoxin persists in the cell and is converted to BmGT, with levels significantly higher than those in the wild type. Similarly, in the ΔgliT strain, gliotoxin oxidation is impeded, and methylation occurs unchecked, leading to significant S-adenosylmethionine (SAM) depletion and S-adenosylhomocysteine (SAH) overproduction. This in turn significantly contributes to the observed hypersensitivity of gliT-deficient A. fumigatus to gliotoxin. Our observations reveal a key role for GliT in preventing dysregulation of the methyl/methionine cycle to control intracellular SAM and SAH homeostasis during gliotoxin biosynthesis and exposure. Moreover, we reveal attenuated GliT abundance in the A. fumigatus ΔgliK strain, but not the ΔgliG strain, following exposure to gliotoxin, correlating with relative sensitivities. Overall, we illuminate new systems interactions that have evolved in gliotoxin-producing, compared to gliotoxin-naive, fungi to facilitate their cellular presence.

Dataset Information

Gliotoxin Induces Cofilin Phosphorylation to Promote Actin Cytoskeleton Dynamics and Internalization of Aspergillus fumigatus Into Type II Human Pneumocyte Cells.

Publications

Gliotoxin Induces Cofilin Phosphorylation to Promote Actin Cytoskeleton Dynamics and Internalization of <i>Aspergillus fumigatus</i> Into Type II Human Pneumocyte Cells.

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