MicroRNA exporter HuR clears the internalized pathogens by promoting pro‐inflammatory response in infected macrophages
Abstract HuR is a miRNA derepressor protein that can act as miRNA sponge for specific miRNAs to negate their action on target mRNAs. Here we have identified how HuR, by inducing extracellular vesicles‐mediated export of miRNAs, ensures robust derepression of miRNA‐repressed cytokines essential for s...
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doaj-d0af691615a6445d97fb019a7848feca2021-08-02T16:53:03ZengWileyEMBO Molecular Medicine1757-46761757-46842020-03-01123n/an/a10.15252/emmm.201911011MicroRNA exporter HuR clears the internalized pathogens by promoting pro‐inflammatory response in infected macrophagesAvijit Goswami0Kamalika Mukherjee1Anup Mazumder2Satarupa Ganguly3Ishita Mukherjee4Saikat Chakrabarti5Syamal Roy6Shyam Sundar7Krishnananda Chattopadhyay8Suvendra N Bhattacharyya9RNA Biology Research Laboratory Molecular Genetics Division CSIR‐Indian Institute of Chemical Biology Kolkata IndiaRNA Biology Research Laboratory Molecular Genetics Division CSIR‐Indian Institute of Chemical Biology Kolkata IndiaRNA Biology Research Laboratory Molecular Genetics Division CSIR‐Indian Institute of Chemical Biology Kolkata IndiaRNA Biology Research Laboratory Molecular Genetics Division CSIR‐Indian Institute of Chemical Biology Kolkata IndiaStructural Biology and Bio‐informatics Division CSIR‐Indian Institute of Chemical Biology Kolkata IndiaStructural Biology and Bio‐informatics Division CSIR‐Indian Institute of Chemical Biology Kolkata IndiaNational Institute of Pharmaceutical Educations and Research Kolkata IndiaDepartment of Medicine Banaras Hindu University Varanasi IndiaStructural Biology and Bio‐informatics Division CSIR‐Indian Institute of Chemical Biology Kolkata IndiaRNA Biology Research Laboratory Molecular Genetics Division CSIR‐Indian Institute of Chemical Biology Kolkata IndiaAbstract HuR is a miRNA derepressor protein that can act as miRNA sponge for specific miRNAs to negate their action on target mRNAs. Here we have identified how HuR, by inducing extracellular vesicles‐mediated export of miRNAs, ensures robust derepression of miRNA‐repressed cytokines essential for strong pro‐inflammatory response in activated mammalian macrophages. Leishmania donovani, the causative agent of visceral leishmaniasis, on the contrary alters immune response of the host macrophage by a variety of complex mechanisms to promote anti‐inflammatory response essential for the survival of the parasite. We have found that during Leishmania infection, the pathogen targets HuR to promote onset of anti‐inflammatory response in mammalian macrophages. In infected macrophages, Leishmania also upregulate protein phosphatase 2A that acts on Ago2 protein to keep it in dephosphorylated and miRNA‐associated form. This causes robust repression of the miRNA‐targeted pro‐inflammatory cytokines to establish an anti‐inflammatory response in infected macrophages. HuR has an inhibitory effect on protein phosphatase 2A expression, and mathematical modelling of macrophage activation process supports antagonistic miRNA‐modulatory roles of HuR and protein phosphatase 2A which mutually balances immune response in macrophage by targeting miRNA function. Supporting this model, ectopic expression of the protein HuR and simultaneous inhibition of protein phosphatase 2A induce strong pro‐inflammatory response in the host macrophage to prevent the virulent antimonial drug‐sensitive or drug‐resistant form of L. donovani infection. Thus, HuR can act as a balancing factor of immune responses to curtail the macrophage infection process by the protozoan parasite.https://doi.org/10.15252/emmm.201911011Ago2 dephosphorylationdrug‐resistant Leishmaniahost–parasite interactionmiRNA exportprotein phosphatase 2A |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Avijit Goswami Kamalika Mukherjee Anup Mazumder Satarupa Ganguly Ishita Mukherjee Saikat Chakrabarti Syamal Roy Shyam Sundar Krishnananda Chattopadhyay Suvendra N Bhattacharyya |
spellingShingle |
Avijit Goswami Kamalika Mukherjee Anup Mazumder Satarupa Ganguly Ishita Mukherjee Saikat Chakrabarti Syamal Roy Shyam Sundar Krishnananda Chattopadhyay Suvendra N Bhattacharyya MicroRNA exporter HuR clears the internalized pathogens by promoting pro‐inflammatory response in infected macrophages EMBO Molecular Medicine Ago2 dephosphorylation drug‐resistant Leishmania host–parasite interaction miRNA export protein phosphatase 2A |
author_facet |
Avijit Goswami Kamalika Mukherjee Anup Mazumder Satarupa Ganguly Ishita Mukherjee Saikat Chakrabarti Syamal Roy Shyam Sundar Krishnananda Chattopadhyay Suvendra N Bhattacharyya |
author_sort |
Avijit Goswami |
title |
MicroRNA exporter HuR clears the internalized pathogens by promoting pro‐inflammatory response in infected macrophages |
title_short |
MicroRNA exporter HuR clears the internalized pathogens by promoting pro‐inflammatory response in infected macrophages |
title_full |
MicroRNA exporter HuR clears the internalized pathogens by promoting pro‐inflammatory response in infected macrophages |
title_fullStr |
MicroRNA exporter HuR clears the internalized pathogens by promoting pro‐inflammatory response in infected macrophages |
title_full_unstemmed |
MicroRNA exporter HuR clears the internalized pathogens by promoting pro‐inflammatory response in infected macrophages |
title_sort |
microrna exporter hur clears the internalized pathogens by promoting pro‐inflammatory response in infected macrophages |
publisher |
Wiley |
series |
EMBO Molecular Medicine |
issn |
1757-4676 1757-4684 |
publishDate |
2020-03-01 |
description |
Abstract HuR is a miRNA derepressor protein that can act as miRNA sponge for specific miRNAs to negate their action on target mRNAs. Here we have identified how HuR, by inducing extracellular vesicles‐mediated export of miRNAs, ensures robust derepression of miRNA‐repressed cytokines essential for strong pro‐inflammatory response in activated mammalian macrophages. Leishmania donovani, the causative agent of visceral leishmaniasis, on the contrary alters immune response of the host macrophage by a variety of complex mechanisms to promote anti‐inflammatory response essential for the survival of the parasite. We have found that during Leishmania infection, the pathogen targets HuR to promote onset of anti‐inflammatory response in mammalian macrophages. In infected macrophages, Leishmania also upregulate protein phosphatase 2A that acts on Ago2 protein to keep it in dephosphorylated and miRNA‐associated form. This causes robust repression of the miRNA‐targeted pro‐inflammatory cytokines to establish an anti‐inflammatory response in infected macrophages. HuR has an inhibitory effect on protein phosphatase 2A expression, and mathematical modelling of macrophage activation process supports antagonistic miRNA‐modulatory roles of HuR and protein phosphatase 2A which mutually balances immune response in macrophage by targeting miRNA function. Supporting this model, ectopic expression of the protein HuR and simultaneous inhibition of protein phosphatase 2A induce strong pro‐inflammatory response in the host macrophage to prevent the virulent antimonial drug‐sensitive or drug‐resistant form of L. donovani infection. Thus, HuR can act as a balancing factor of immune responses to curtail the macrophage infection process by the protozoan parasite. |
topic |
Ago2 dephosphorylation drug‐resistant Leishmania host–parasite interaction miRNA export protein phosphatase 2A |
url |
https://doi.org/10.15252/emmm.201911011 |
work_keys_str_mv |
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