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The Mitogen-activated protein kinase p38 links Shiga Toxin-dependent signaling and trafficking.

ABSTRACT: Shiga toxin (Stx) binds to the cell, and it is transported via endosomes and the Golgi apparatus to the endoplasmic reticulum and cytosol, where it exerts its toxic effect. We have recently shown that Stx activates the tyrosine kinase Syk, which in turn induces clathrin phosphorylation and up-regulates Stx uptake. Here, we show that toxin-induced signaling can also regulate another step in intracellular Stx transport. We demonstrate that transport of Stx to the Golgi apparatus is dependent on the mitogen-activated protein kinase p38. Treatment of cells with chemical inhibitors or small interfering RNA targeting p38 inhibited Stx transport to the Golgi and reduced Stx toxicity. This p38 dependence is specific to Stx, because transport of the related toxin ricin was not affected by p38 inhibition. Stx rapidly activated p38, and recruited it to early endosomes in a Ca(2+)-dependent manner. Furthermore, agonist-induced oscillations in cytosolic Ca(2+) levels were inhibited upon Stx stimulation, possibly reflecting Stx-dependent local alterations in cytosolic Ca(2+) levels. Intracellular transport of Stx is Ca(2+) dependent, and we provide evidence that Stx activates a signaling cascade involving cross talk between Ca(2+) and p38, to regulate its trafficking to the Golgi apparatus.

SUBMITTER: Walchli S

PROVIDER: S-EPMC2174185 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

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The Mitogen-activated protein kinase p38 links Shiga Toxin-dependent signaling and trafficking.

Wälchli Sébastien S Skånland Sigrid S SS Gregers Tone F TF Lauvrak Silje U SU Torgersen Maria L ML Ying Ming M Kuroda Shun'ichi S Maturana Andrés A Sandvig Kirsten K

Molecular biology of the cell 20071024 1

Shiga toxin (Stx) binds to the cell, and it is transported via endosomes and the Golgi apparatus to the endoplasmic reticulum and cytosol, where it exerts its toxic effect. We have recently shown that Stx activates the tyrosine kinase Syk, which in turn induces clathrin phosphorylation and up-regulates Stx uptake. Here, we show that toxin-induced signaling can also regulate another step in intracellular Stx transport. We demonstrate that transport of Stx to the Golgi apparatus is dependent on th ...[more]

PMID: 17959827

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Project description:Radiation biodosimetry based on transcriptomic analysis of peripheral blood is a valuable tool to detect radiation exposure after a radiological/nuclear event and obtain useful biological information that could predict tissue and organismal injury. However, confounding factors, including chronic inflammation or immune suppression, can potentially obscure the predictive power of the method. Members of the p38 mitogen-activated protein kinase (MAPK) family respond to pro-inflammatory signals and environmental stresses, whereas genetic ablation of the p38 signaling pathway in mice leads to reduced susceptibility to collagen-induced arthritis and experimental autoimmune encephalomyelitis that model human rheumatoid arthritis and multiple sclerosis, respectively. p38 is normally regulated by the MAP3K-MAP2K pathway in mammalian cells. However, in T cells there is an alternative pathway for p38 activation that plays an important role in antigen-receptor-activated T cells and participates in immune and inflammatory responses. To examine the role of p38 in response to radiation, we used two mouse models expressing either a p38α dominant negative (DN) mutation that globally suppresses p38 signaling or a p38αβ double-knock-in (DKI) mutant, which inhibits specifically T-cell receptor activation. We exposed p38 wild-type (p38WT) and mutant male mice to 7 Gy X rays and 24 h later whole blood was isolated subjected to whole-genome microarray and gene ontology analysis. Irradiation of p38WT mice led to a significant overrepresentation of pathways associated with morbidity and mortality, as well as organismal cell death. In contrast, these pathways were significantly underrepresented in p38DN and p38DKI mutant mice, suggesting that p38 attenuation may protect blood cells from the deleterious effects of radiation. Furthermore, radiation exposure in p38 mutant mice resulted in an enrichment of phagocytosis-related pathways, suggesting a role for p38 signaling in restricting phagocytosis of apoptotic cells after irradiation. Finally, despite the significant changes in gene expression, it was still feasible to identify a panel of genes that could accurately distinguish between irradiated and control mice, irrespective of p38 status.

Project description:Radiation biodosimetry based on transcriptomic analysis of peripheral blood is a valuable tool to detect radiation exposure after a radiological/nuclear event and obtain useful biological information that could predict tissue and organismal injury. However, confounding factors, including inflammation, can potentially obscure the predictive power of the method. The mitogen-activated protein kinase (MAPK) p38 is normally regulated by the MAP3K-MAP2K pathway in mammalian cells. Members of the p38 MAPK family respond to pro-inflammatory signals and environmental stresses. However, in T cells there is an alternative pathway for p38MAPK activation. This pathway has been shown to play an important role in antigen-receptor-activated T cells and participate in immune and inflammatory responses. Radiation is known to induce a pro-inflammatory response. To examine the role of p38MAPK in response to radiation, we used two mouse models expressing either a p38αMAPK dominant negative (DN) mutation that would be expected to globally suppress p38MAPK signaling or a double knock-in (DKI) mutant, which would be expected to inhibit specifically T cell receptor activation. We exposed wild-type and p38MAPK mutant mice to 7 Gy x-rays and 24 h later we isolated whole blood and performed genome microarray and gene ontology analysis. Comparison between the two mutants (DN, DKI) suggest that the alternative p38MAPK pathway may have wider functions in the response to radiation exposure beyond its well established role as a downstream effector of activated T-cell receptor. Among the differentially enriched pathways, irradiation leads to a significant overrepresentation of pathways associated with morbidity and mortality as well as organismal cell death. In contrast, these pathways were significantly underrepresented in p38MAPKDN and p38MAPKDKI mutant mice, implying that p38MAPK suppression protects mice from the deleterious effects of radiation. Furthermore, radiation exposure resulted in an enrichment of a small number of phagocytosis-related pathways; however, considerably more phagocytosis-related pathways were overrepresented in the p38MAPK mutant mice, implying that p38MAPK signaling, normally, restricts phagocytosis of apoptotic cells after radiation and may, thus, contribute to persistent inflammation. Finally, despite the significant changes in gene expression, we were still able to identify a panel of genes that could accurately distinguish between irradiated and control mice, irrespective of p38MAPK status.

Dataset Information

The Mitogen-activated protein kinase p38 links Shiga Toxin-dependent signaling and trafficking.

Publications

The Mitogen-activated protein kinase p38 links Shiga Toxin-dependent signaling and trafficking.

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