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Mitogen-activated protein kinases (MAPKs) regulate IL-6 over-production during concomitant influenza virus and Staphylococcus aureus infection.

ABSTRACT: Bacterial super-infections are a major complication of influenza virus (IV) infections and often lead to severe pneumonia. One hallmark of IV-associated Staphylococcus aureus (S. aureus) infection is rapid progression to a serious disease outcome. Changes in immune and inflammatory host responses increase morbidity and complicate efficient therapy. A key player during inflammation is the multifunctional cytokine IL-6. Although increased IL-6 levels have been observed after severe disease upon IV and/or bacterial super-infection, the underlying molecular mechanisms still remain to be elucidated. In the present study, we focused on cellular signalling pathways regulating IL-6 production upon IV/S. aureus super-infection. Additionally, infection with viable bacteria was mimicked by lipoteichoic acid stimulation in this model. Analyses of cellular signalling mechanisms revealed synergistically increased activation of the MAPK p38 as well as enhanced phosphorylation of the MAPKs ERK1/2 and JNK in the presence of super-infecting bacteria. Interestingly, inhibition of MAPK activity indicated a strong dependence of IL-6 expression on p38 and ERK1/2, while the MAPK JNK seems not to be involved. Thus, our results provide new molecular insights into the regulation of IL-6, a marker of severe disease, which might contribute to the lethal synergism of IV and S. aureus.

SUBMITTER: Klemm C

PROVIDER: S-EPMC5307969 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Mitogen-Activated Protein Kinases (MAPKs) and Cholangiocarcinoma: The Missing Link.

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| S-EPMC5397809 | biostudies-other

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Src Family Kinases and p38 Mitogen-Activated Protein Kinases Regulate Pluripotent Cell Differentiation in Culture.

Project description:Multiple pluripotent cell populations, which together comprise the pluripotent cell lineage, have been identified. The mechanisms that control the progression between these populations are still poorly understood. The formation of early primitive ectoderm-like (EPL) cells from mouse embryonic stem (mES) cells provides a model to understand how one such transition is regulated. EPL cells form from mES cells in response to l-proline uptake through the transporter Slc38a2. Using inhibitors of cell signaling we have shown that Src family kinases, p38 MAPK, ERK1/2 and GSK3? are required for the transition between mES and EPL cells. ERK1/2, c-Src and GSK3? are likely to be enforcing a receptive, primed state in mES cells, while Src family kinases and p38 MAPK are involved in the establishment of EPL cells. Inhibition of these pathways prevented the acquisition of most, but not all, features of EPL cells, suggesting that other pathways are required. L-proline activation of differentiation is mediated through metabolism and changes to intracellular metabolite levels, specifically reactive oxygen species. The implication of multiple signaling pathways in the process suggests a model in which the context of Src family kinase activation determines the outcomes of pluripotent cell differentiation.

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Project description:Using a systems-based approach, we have identified several genes not previously evaluated for a role(s) in chronological aging. Here, we have thoroughly investigated the chronological lifespan (CLS) of three of these genes (FUS3, KSS1 and HOG1) and their protein products, each of which have well-defined cell signaling roles in young cells. The importance of FUS3 and KSS1 in CLS are largely unknown and analyzed here for the first time. Using both qualitative and quantitative CLS assays, we show that deletion of any of the three MAPK's increases yeast lifespan. Furthermore, combined deletion of any MAPK and TOR1, most prominently fus3?/tor1?, produces a two-stage CLS response ending in lifespan increase greater than that of tor1?. Similar effects are achieved upon endogenous expression of a non-activatable form of Fus3. We speculate that the autophagy-promoting role of FUS3, which is inherently antagonistic to the role of TOR1, may in part be responsible for the differential aging phenotype of fus3?/tor1?. Consistent with this notion we show that nitrogen starvation, which promotes autophagy by deactivating Tor1, results in decreased CLS if FUS3 is deleted. Taken together, these results reveal a previously unrealized effect of mating-specific MAPKs in the chronological lifespan of yeast.

| S-EPMC5764394 | biostudies-literature

Quantitative Phosphoproteomic Analysis Reveals Shared and Specific Targets of Arabidopsis Mitogen-Activated Protein Kinases (MAPKs) MPK3, MPK4, and MPK6.

Project description:In Arabidopsis, mitogen-activated protein kinases MPK3, MPK4, and MPK6 constitute essential relays for a variety of functions including cell division, development and innate immunity. Although some substrates of MPK3, MPK4 and MPK6 have been identified, the picture is still far from complete. To identify substrates of these MAPKs likely involved in cell division, growth and development we compared the phosphoproteomes of wild-type and mpk3, mpk4, and mpk6. To study the function of these MAPKs in innate immunity, we analyzed their phosphoproteomes following microbe-associated molecular pattern (MAMP) treatment. Partially overlapping substrates were retrieved for all three MAPKs, showing target specificity to one, two or all three MAPKs in different biological processes. More precisely, our results illustrate the fact that the entity to be defined as a specific or a shared substrate for MAPKs is not a phosphoprotein but a particular (S/T)P phosphorylation site in a given protein. One hundred fifty-two peptides were identified to be differentially phosphorylated in response to MAMP treatment and/or when compared between genotypes and 70 of them could be classified as putative MAPK targets. Biochemical analysis of a number of putative MAPK substrates by phosphorylation and interaction assays confirmed the global phosphoproteome approach. Our study also expands the set of MAPK substrates to involve other protein kinases, including calcium-dependent (CDPK) and sugar nonfermenting (SnRK) protein kinases.

| S-EPMC5750851 | biostudies-literature

SUMO enables substrate selectivity by mitogen-activated protein kinases to regulate immunity in plants.

Project description:The versatility of mitogen-activated protein kinases (MAPKs) in translating exogenous and endogenous stimuli into appropriate cellular responses depends on its substrate specificity. In animals, several mechanisms have been proposed about how MAPKs maintain specificity to regulate distinct functional pathways. However, little is known of mechanisms that enable substrate selectivity in plant MAPKs. Small ubiquitin-like modifier (SUMO), a posttranslational modification system, plays an important role in plant development and defense by rapid reprogramming of cellular events. In this study we identified a functional SUMO interaction motif (SIM) in Arabidopsis MPK3 and MPK6 that reveals a mechanism for selective interaction of MPK3/6 with SUMO-conjugated WRKY33, during defense. We show that WRKY33 is rapidly SUMOylated in response to Botrytis cinerea infection and flg22 elicitor treatment. SUMOylation mediates WRKY33 phosphorylation by MPKs and consequent transcription factor activity. Disruption of either WRKY33 SUMO or MPK3/6 SIM sites attenuates their interaction and inactivates WRKY33-mediated defense. However, MPK3/6 SIM mutants show normal interaction with a non-SUMOylated form of another transcription factor, SPEECHLESS, unraveling a role for SUMOylation in differential substrate selectivity by MPKs. We reveal that the SUMO proteases, SUMO PROTEASE RELATED TO FERTILITY1 (SPF1) and SPF2 control WRKY33 SUMOylation and demonstrate a role for these SUMO proteases in defense. Our data reveal a mechanism by which MPK3/6 prioritize molecular pathways by differentially selecting substrates using the SUMO-SIM module during defense responses.

| S-EPMC7958252 | biostudies-literature

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