Reprogramming of microRNA expression via E2F1 downregulation promotes Salmonella infection both in infected and bystander cells

Carmen Aguilar; Susana Costa; Claire Maudet; R. P. Vivek-Ananth; Sara Zaldívar-López; Juan J. Garrido; Areejit Samal; Miguel Mano; Ana Eulalio

doi:10.1038/s41467-021-23593-z

Reprogramming of microRNA expression via E2F1 downregulation promotes Salmonella infection both in infected and bystander cells

Carmen Aguilar, Susana Costa, Claire Maudet, R. P. Vivek-Ananth, Sara Zaldívar-López, Juan J. Garrido, Areejit Samal, Miguel Mano, Ana Eulalio^*

^*Corresponding author for this work

Cardiovascular Sciences

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

Abstract

Cells infected with pathogens can contribute to clearing infections by releasing signals that instruct neighbouring cells to mount a pro-inflammatory cytokine response, or by other mechanisms that reduce bystander cells’ susceptibility to infection. Here, we show the opposite effect: epithelial cells infected with Salmonella Typhimurium secrete host factors that facilitate the infection of bystander cells. We find that the endoplasmic reticulum stress response is activated in both infected and bystander cells, and this leads to activation of JNK pathway, downregulation of transcription factor E2F1, and consequent reprogramming of microRNA expression in a time-dependent manner. These changes are not elicited by infection with other bacterial pathogens, such as Shigella flexneri or Listeria monocytogenes. Remarkably, the protein HMGB1 present in the secretome of Salmonella-infected cells is responsible for the activation of the IRE1 branch of the endoplasmic reticulum stress response in non-infected, neighbouring cells. Furthermore, E2F1 downregulation and the associated microRNA alterations promote Salmonella replication within infected cells and prime bystander cells for more efficient infection.

Original language	English
Article number	3392
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-23593-z
Publication status	Published - Dec 2021

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@article{ed1db3385f2249d1a60e1efda709cb03,

title = "Reprogramming of microRNA expression via E2F1 downregulation promotes Salmonella infection both in infected and bystander cells",

abstract = "Cells infected with pathogens can contribute to clearing infections by releasing signals that instruct neighbouring cells to mount a pro-inflammatory cytokine response, or by other mechanisms that reduce bystander cells{\textquoteright} susceptibility to infection. Here, we show the opposite effect: epithelial cells infected with Salmonella Typhimurium secrete host factors that facilitate the infection of bystander cells. We find that the endoplasmic reticulum stress response is activated in both infected and bystander cells, and this leads to activation of JNK pathway, downregulation of transcription factor E2F1, and consequent reprogramming of microRNA expression in a time-dependent manner. These changes are not elicited by infection with other bacterial pathogens, such as Shigella flexneri or Listeria monocytogenes. Remarkably, the protein HMGB1 present in the secretome of Salmonella-infected cells is responsible for the activation of the IRE1 branch of the endoplasmic reticulum stress response in non-infected, neighbouring cells. Furthermore, E2F1 downregulation and the associated microRNA alterations promote Salmonella replication within infected cells and prime bystander cells for more efficient infection.",

author = "Carmen Aguilar and Susana Costa and Claire Maudet and Vivek-Ananth, {R. P.} and Sara Zald{\'i}var-L{\'o}pez and Garrido, {Juan J.} and Areejit Samal and Miguel Mano and Ana Eulalio",

note = "Funding Information: C.A. is a recipient of a fellowship from the Bayerischen Gleichstellungsf{\"o}rderung (BGF) through the SCIENTIA Program and S.C. is a recipient of a Ph.D. scholarship from the Portuguese Foundation for Science and Technology (2020.06572.BD). The authors acknowledge the EMBL Proteomics Core facility (in particular Mandy Rettel and Frank Stein), the EMBL Genomics Core facility (in particular Vladimir Benes and Nayara Trevisan Doimo de Azevedo), and the Animal facility at the University of Leon, Spain (in particular Ana Carvajal from the Department of Animal Health). This work was supported by grants from the Bavarian Ministry of Sciences, Research and the Arts in the framework of the Bavarian Molecular Biosystems Research Network (BioSysNet), DFG project BR 4837/1-1, ERDF - European Regional Development Fund through COMPETE 2020 and the Portuguese Foundation for Science and Technology (POCI-01-0145-FEDER-007440, UIDB/ 04539/2020, and FCT Investigator Programme IF/01105/2015) to A.E., and the Science and Engineering Research Board (SERB), Department of Science and Technology (DST), India, Ramanujan fellowship (SB/S2/RJN-006/2014) to A.S., and the Spanish Ministry of Economy and Competitiveness (AGL2017-87415-R) to J.J.G. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

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doi = "10.1038/s41467-021-23593-z",

language = "English",

volume = "12",

journal = "Nature Communications",

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T1 - Reprogramming of microRNA expression via E2F1 downregulation promotes Salmonella infection both in infected and bystander cells

AU - Aguilar, Carmen

AU - Costa, Susana

AU - Maudet, Claire

AU - Vivek-Ananth, R. P.

AU - Zaldívar-López, Sara

AU - Garrido, Juan J.

AU - Samal, Areejit

AU - Mano, Miguel

AU - Eulalio, Ana

N1 - Funding Information: C.A. is a recipient of a fellowship from the Bayerischen Gleichstellungsförderung (BGF) through the SCIENTIA Program and S.C. is a recipient of a Ph.D. scholarship from the Portuguese Foundation for Science and Technology (2020.06572.BD). The authors acknowledge the EMBL Proteomics Core facility (in particular Mandy Rettel and Frank Stein), the EMBL Genomics Core facility (in particular Vladimir Benes and Nayara Trevisan Doimo de Azevedo), and the Animal facility at the University of Leon, Spain (in particular Ana Carvajal from the Department of Animal Health). This work was supported by grants from the Bavarian Ministry of Sciences, Research and the Arts in the framework of the Bavarian Molecular Biosystems Research Network (BioSysNet), DFG project BR 4837/1-1, ERDF - European Regional Development Fund through COMPETE 2020 and the Portuguese Foundation for Science and Technology (POCI-01-0145-FEDER-007440, UIDB/ 04539/2020, and FCT Investigator Programme IF/01105/2015) to A.E., and the Science and Engineering Research Board (SERB), Department of Science and Technology (DST), India, Ramanujan fellowship (SB/S2/RJN-006/2014) to A.S., and the Spanish Ministry of Economy and Competitiveness (AGL2017-87415-R) to J.J.G. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12

Y1 - 2021/12

N2 - Cells infected with pathogens can contribute to clearing infections by releasing signals that instruct neighbouring cells to mount a pro-inflammatory cytokine response, or by other mechanisms that reduce bystander cells’ susceptibility to infection. Here, we show the opposite effect: epithelial cells infected with Salmonella Typhimurium secrete host factors that facilitate the infection of bystander cells. We find that the endoplasmic reticulum stress response is activated in both infected and bystander cells, and this leads to activation of JNK pathway, downregulation of transcription factor E2F1, and consequent reprogramming of microRNA expression in a time-dependent manner. These changes are not elicited by infection with other bacterial pathogens, such as Shigella flexneri or Listeria monocytogenes. Remarkably, the protein HMGB1 present in the secretome of Salmonella-infected cells is responsible for the activation of the IRE1 branch of the endoplasmic reticulum stress response in non-infected, neighbouring cells. Furthermore, E2F1 downregulation and the associated microRNA alterations promote Salmonella replication within infected cells and prime bystander cells for more efficient infection.

AB - Cells infected with pathogens can contribute to clearing infections by releasing signals that instruct neighbouring cells to mount a pro-inflammatory cytokine response, or by other mechanisms that reduce bystander cells’ susceptibility to infection. Here, we show the opposite effect: epithelial cells infected with Salmonella Typhimurium secrete host factors that facilitate the infection of bystander cells. We find that the endoplasmic reticulum stress response is activated in both infected and bystander cells, and this leads to activation of JNK pathway, downregulation of transcription factor E2F1, and consequent reprogramming of microRNA expression in a time-dependent manner. These changes are not elicited by infection with other bacterial pathogens, such as Shigella flexneri or Listeria monocytogenes. Remarkably, the protein HMGB1 present in the secretome of Salmonella-infected cells is responsible for the activation of the IRE1 branch of the endoplasmic reticulum stress response in non-infected, neighbouring cells. Furthermore, E2F1 downregulation and the associated microRNA alterations promote Salmonella replication within infected cells and prime bystander cells for more efficient infection.

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DO - 10.1038/s41467-021-23593-z

M3 - Article

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SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

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Reprogramming of microRNA expression via E2F1 downregulation promotes Salmonella infection both in infected and bystander cells

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