mTORC2 orchestrates monocytic and granulocytic lineage commitment by an ATF5-mediated pathway

Yang Zhao; Chenxu Zhao; Han Guo; Zhaoqi Zhang; Huawen Xu; Mingpu Shi; Yanan Xu; Dong Wei; Yong Zhao

doi:10.1016/j.isci.2023.107540

mTORC2 orchestrates monocytic and granulocytic lineage commitment by an ATF5-mediated pathway

iScience. 2023 Aug 3;26(9):107540. doi: 10.1016/j.isci.2023.107540. eCollection 2023 Sep 15.

Authors

Yang Zhao^{1

2}, Chenxu Zhao^{1

3

4}, Han Guo^{1

3

2}, Zhaoqi Zhang^{1

4}, Huawen Xu^{1

3}, Mingpu Shi^{1

3}, Yanan Xu^{1

3}, Dong Wei^{1

4}, Yong Zhao^{1

3

2

4}

Affiliations

¹ State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
² Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China.
³ University of Chinese Academy of Sciences, Beijing 100049, China.
⁴ Faculty of Synthetic Biology, Shenzhen Institute of Advanced Technology, CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.

Abstract

Myeloid hematopoiesis is a finely controlled consecutive developmental process, which is essential to maintain peripheral innate immune homeostasis. Herein, we found that Rictor deletion caused the remarkable reduction of granulocyte-monocyte progenitors (GMPs), monocytes, and macrophages, while the levels of neutrophils were unaffected. Adoptive transfer of Rictor-deleted GMPs or common myeloid progenitors (CMPs) in syngeneic mice showed poor re-constitution of monocytes compared to wild-type GMPs or CMPs. In addition to decreasing the proliferation of CMPs/GMPs, Rictor deletion preferentially inhibited Ly6C⁺ monocyte differentiation, while enhancing neutrophil differentiation, as determined by colony formation assays. mTORC2 promotes monocyte development by downregulation of the AKT-Foxo4-activating transcription factor 5 (ATF5)-mitochondrial unfolded protein response (mtUPR) pathway. Genetic overexpression of ATF5 or exposure to ethidium bromide significantly rescued monocyte/macrophage differentiation defects of Rictor-deficient myeloid progenitors. Therefore, Rictor is required for CMP/GMP proliferation and acts as an important switch to balance monocytic and granulocytic lineage commitment in bone marrow.

Keywords: Biological sciences; Cell biology; Components of the immune system; Molecular biology.