The amino acid sensor GCN2 controls red blood cell clearance and iron metabolism through regulation of liver macrophages

Phoenix Toboz; Mehdi Amiri; Negar Tabatabaei; Catherine R Dufour; Seung Hyeon Kim; Carine Fillebeen; Charles E Ayemoba; Arkady Khoutorsky; Manfred Nairz; Lijian Shao; Kostandin V Pajcini; Ki-Wook Kim; Vincent Giguère; Regiana L Oliveira; Marco Constante; Manuela M Santos; Carlos R Morales; Kostas Pantopoulos; Nahum Sonenberg; Sandra Pinho; Soroush Tahmasebi

doi:10.1073/pnas.2121251119

The amino acid sensor GCN2 controls red blood cell clearance and iron metabolism through regulation of liver macrophages

Proc Natl Acad Sci U S A. 2022 Aug 30;119(35):e2121251119. doi: 10.1073/pnas.2121251119. Epub 2022 Aug 22.

Authors

Phoenix Toboz¹, Mehdi Amiri^{2

3}, Negar Tabatabaei¹, Catherine R Dufour³, Seung Hyeon Kim¹, Carine Fillebeen⁴, Charles E Ayemoba¹, Arkady Khoutorsky⁵, Manfred Nairz⁶, Lijian Shao¹, Kostandin V Pajcini¹, Ki-Wook Kim¹, Vincent Giguère^{2

3}, Regiana L Oliveira⁷, Marco Constante⁸, Manuela M Santos⁸, Carlos R Morales⁷, Kostas Pantopoulos⁴, Nahum Sonenberg^{2

3}, Sandra Pinho¹, Soroush Tahmasebi¹

Affiliations

¹ Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL, 60612.
² Department of Biochemistry, McGill University, Montreal, QC, H3A 1A3, Canada.
³ Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC, H3A 1A3, Canada.
⁴ Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, QC, H3T 1E2, Canada.
⁵ Department of Anesthesia and Faculty of Dentistry, McGill University, Montreal, QC, H3A 0G1, Canada.
⁶ Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, 6020, Austria.
⁷ Department of Anatomy and Cell Biology, McGill University, Montreal, QC, H3G 1Y6, Canada.
⁸ Nutrition and Microbiome Laboratory, Centre de recherche du CHUM and Department of Medicine, Université de Montréal, Montréal, QC, H3X 0A9, Canada.

Abstract

GCN2 (general control nonderepressible 2) is a serine/threonine-protein kinase that controls messenger RNA translation in response to amino acid availability and ribosome stalling. Here, we show that GCN2 controls erythrocyte clearance and iron recycling during stress. Our data highlight the importance of liver macrophages as the primary cell type mediating these effects. During different stress conditions, such as hemolysis, amino acid deficiency or hypoxia, GCN2 knockout (GCN2^-/-) mice displayed resistance to anemia compared with wild-type (GCN2^+/+) mice. GCN2^-/- liver macrophages exhibited defective erythrophagocytosis and lysosome maturation. Molecular analysis of GCN2^-/- cells demonstrated that the ATF4-NRF2 pathway is a critical downstream mediator of GCN2 in regulating red blood cell clearance and iron recycling.

Keywords: GCN2; RBC; hemolytic stress; mRNA translation; macrophages.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Activating Transcription Factor 4 / metabolism
Amino Acids* / deficiency
Amino Acids* / metabolism
Anemia / metabolism
Animals
Cytophagocytosis
Erythrocytes* / metabolism
Gene Deletion
Hemolysis
Hypoxia / metabolism
Iron* / metabolism
Liver* / cytology
Lysosomes / metabolism
Macrophages* / metabolism
Mice
Mice, Knockout
NF-E2-Related Factor 2 / metabolism
Protein Serine-Threonine Kinases* / deficiency
Protein Serine-Threonine Kinases* / genetics
Protein Serine-Threonine Kinases* / metabolism
Stress, Physiological

Substances

Amino Acids
Atf4 protein, mouse
NF-E2-Related Factor 2
Nfe2l2 protein, mouse
Activating Transcription Factor 4
Iron
Eif2ak4 protein, mouse
Protein Serine-Threonine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding