Involvement of the p62/NRF2 signal transduction pathway on erythrophagocytosis

I.B. Santarino, M.S. Viegas, N.S. Domingues, A.M. Ribeiro, M.P. Soares, O.V. Vieira

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Abstract

Erythrophagocytosis, the phagocytic removal of damaged red blood cells (RBC), and subsequent phagolysosome biogenesis are important processes in iron/heme metabolism and homeostasis. Phagolysosome biogenesis implies the interaction of nascent phagosomes with endocytic compartments and also autophagy effectors. Here, we report that besides recruitment of microtubule-associated protein-1-light chain 3 (LC3), additional autophagy machinery such as sequestosome 1 (p62) is also acquired by single-membrane phagosomes at very early stages of the phagocytic process and that its acquisition is very important to the outcome of the process. In bone marrow-derived macrophages (BMDM) silenced for p62, RBC degradation is inhibited. P62, is also required for nuclear translocation and activation of the transcription factor Nuclear factor E2-related Factor 2 (NRF2) during erythrophagocytosis. Deletion of the Nrf2 allele reduces p62 expression and compromises RBC degradation. In conclusion, we reveal that erythrophagocytosis relies on an interplay between p62 and NRF2, potentially acting as protective mechanism to maintain reactive oxygen species at basal levels and preserve macrophage homeostasis. © 2017 The Author(s).
Original languageEnglish
Pages (from-to)Online
Number of pages16
JournalScientific Reports
Volume7
Issue number1
DOIs
Publication statusPublished - 19 Jul 2017

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NF-E2-Related Factor 2
Phagosomes
Signal Transduction
Erythrocytes
Autophagy
Homeostasis
Macrophages
Microtubule-Associated Proteins
Heme
Reactive Oxygen Species
Transcription Factors
Iron
Alleles
Light
Membranes

Cite this

@article{c87249abfc034212be7a995f0ced87c6,
title = "Involvement of the p62/NRF2 signal transduction pathway on erythrophagocytosis",
abstract = "Erythrophagocytosis, the phagocytic removal of damaged red blood cells (RBC), and subsequent phagolysosome biogenesis are important processes in iron/heme metabolism and homeostasis. Phagolysosome biogenesis implies the interaction of nascent phagosomes with endocytic compartments and also autophagy effectors. Here, we report that besides recruitment of microtubule-associated protein-1-light chain 3 (LC3), additional autophagy machinery such as sequestosome 1 (p62) is also acquired by single-membrane phagosomes at very early stages of the phagocytic process and that its acquisition is very important to the outcome of the process. In bone marrow-derived macrophages (BMDM) silenced for p62, RBC degradation is inhibited. P62, is also required for nuclear translocation and activation of the transcription factor Nuclear factor E2-related Factor 2 (NRF2) during erythrophagocytosis. Deletion of the Nrf2 allele reduces p62 expression and compromises RBC degradation. In conclusion, we reveal that erythrophagocytosis relies on an interplay between p62 and NRF2, potentially acting as protective mechanism to maintain reactive oxygen species at basal levels and preserve macrophage homeostasis. {\circledC} 2017 The Author(s).",
author = "I.B. Santarino and M.S. Viegas and N.S. Domingues and A.M. Ribeiro and M.P. Soares and O.V. Vieira",
note = "info:eu-repo/grantAgreement/FCT/5876/147260/PT# info:eu-repo/grantAgreement/FCT/SFRH/SFRH{\%}2FBD{\%}2F62197{\%}2F2009/PT# info:eu-repo/grantAgreement/FCT/SFRH/SFRH{\%}2FBD{\%}2F90258{\%}2F2012/PT# info:eu-repo/grantAgreement/FCT/SFRH/SFRH{\%}2FBD{\%}2F51877{\%}2F2012/PT# We would like to thank Prof. Ira Tabas (Columbia University, New York, NY, USA) for providing the L929 cell line, Prof. Herbert Virgin (Washington University, St. Louis, MO, USA) for providing p62-KO mice legs, Dr. H. Girao (CNC. IBILI, Univ. of Coimbra) for the E1-inhibitor and T. Pereira for technical assistance with microscopy. This work was supported by the Foundation for Science and Technology of the Portuguese Ministry of Science and Higher Education [HMSP-ICT/0024/2010, co-founded by the European Union (FEDER - Fundo Europeu de Desenvolvimento Regional) through COMPETE - Programa Operacional Factores de Competitividade and QREN - Quadro de Referencia Estrategico], iNOVA4Health - UID/Multi/04462/2013, a program financially supported by FCT through national funds and co-funded by FEDER under the PT2020 Partnership Agreement and FCT to OVV. PhD fellowships SFRH/BD/62197/2009, SFRH/BD/90258/2012 and SFRH/BD/51877/2012 and SFRH/BD/52293/2013. PTDC/SAU-TOX/116627/2010, HMSP-ICT/0022/2010, European Community 7th Framework Grant ERC-2011-AdG 294709-DAMAGECONTROL to MPS. Editor",
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Involvement of the p62/NRF2 signal transduction pathway on erythrophagocytosis. / Santarino, I.B.; Viegas, M.S.; Domingues, N.S.; Ribeiro, A.M.; Soares, M.P.; Vieira, O.V.

In: Scientific Reports, Vol. 7, No. 1, 19.07.2017, p. Online.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Involvement of the p62/NRF2 signal transduction pathway on erythrophagocytosis

AU - Santarino, I.B.

AU - Viegas, M.S.

AU - Domingues, N.S.

AU - Ribeiro, A.M.

AU - Soares, M.P.

AU - Vieira, O.V.

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N2 - Erythrophagocytosis, the phagocytic removal of damaged red blood cells (RBC), and subsequent phagolysosome biogenesis are important processes in iron/heme metabolism and homeostasis. Phagolysosome biogenesis implies the interaction of nascent phagosomes with endocytic compartments and also autophagy effectors. Here, we report that besides recruitment of microtubule-associated protein-1-light chain 3 (LC3), additional autophagy machinery such as sequestosome 1 (p62) is also acquired by single-membrane phagosomes at very early stages of the phagocytic process and that its acquisition is very important to the outcome of the process. In bone marrow-derived macrophages (BMDM) silenced for p62, RBC degradation is inhibited. P62, is also required for nuclear translocation and activation of the transcription factor Nuclear factor E2-related Factor 2 (NRF2) during erythrophagocytosis. Deletion of the Nrf2 allele reduces p62 expression and compromises RBC degradation. In conclusion, we reveal that erythrophagocytosis relies on an interplay between p62 and NRF2, potentially acting as protective mechanism to maintain reactive oxygen species at basal levels and preserve macrophage homeostasis. © 2017 The Author(s).

AB - Erythrophagocytosis, the phagocytic removal of damaged red blood cells (RBC), and subsequent phagolysosome biogenesis are important processes in iron/heme metabolism and homeostasis. Phagolysosome biogenesis implies the interaction of nascent phagosomes with endocytic compartments and also autophagy effectors. Here, we report that besides recruitment of microtubule-associated protein-1-light chain 3 (LC3), additional autophagy machinery such as sequestosome 1 (p62) is also acquired by single-membrane phagosomes at very early stages of the phagocytic process and that its acquisition is very important to the outcome of the process. In bone marrow-derived macrophages (BMDM) silenced for p62, RBC degradation is inhibited. P62, is also required for nuclear translocation and activation of the transcription factor Nuclear factor E2-related Factor 2 (NRF2) during erythrophagocytosis. Deletion of the Nrf2 allele reduces p62 expression and compromises RBC degradation. In conclusion, we reveal that erythrophagocytosis relies on an interplay between p62 and NRF2, potentially acting as protective mechanism to maintain reactive oxygen species at basal levels and preserve macrophage homeostasis. © 2017 The Author(s).

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