The amino acid sensor GCN2 controls red blood cell clearance and iron metabolism through regulation of liver macrophages-Reference-Cited by-同舟云学术

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

Published:2022-08-22 Issue:35 Volume:119 Page:
ISSN:0027-8424
Container-title:Proceedings of the National Academy of Sciences
language:en
Short-container-title:Proc. Natl. Acad. Sci. U.S.A.

Author:

Toboz Phoenix¹,Amiri Mehdi²³,Tabatabaei Negar¹,Dufour Catherine R.³,Kim Seung Hyeon¹,Fillebeen Carine⁴,Ayemoba Charles E.¹,Khoutorsky Arkady⁵,Nairz Manfred⁶,Shao Lijian¹,Pajcini Kostandin V.¹^ORCID,Kim Ki-Wook¹,Giguère Vincent²³,Oliveira Regiana L.⁷,Constante Marco⁸,Santos Manuela M.⁸,Morales Carlos R.⁷,Pantopoulos Kostas⁴^ORCID,Sonenberg Nahum²³^ORCID,Pinho Sandra¹,Tahmasebi Soroush¹^ORCID

Affiliation:

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,GCN2knockout (GCN2−/−) mice displayed resistance to anemia compared with wild-type (GCN2+/+) mice.GCN2−/−liver macrophages exhibited defective erythrophagocytosis and lysosome maturation. Molecular analysis ofGCN2−/−cells demonstrated that the ATF4-NRF2 pathway is a critical downstream mediator of GCN2 in regulating red blood cell clearance and iron recycling.

Funder

Chicago Community Trust

Gouvernement du Canada | Canadian Institutes of Health Research

HHS | NIH | National Heart, Lung, and Blood Institute

HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

Link

https://pnas.org/doi/pdf/10.1073/pnas.2121251119

Reference77 articles.