The Cytosolic Protein G0S2 Maintains Quiescence in Hematopoietic Stem Cells

Abstract

Bone marrow hematopoietic stem cells (HSCs) balance proliferation and differentiation by integrating complex transcriptional and post-translational mechanisms regulated by cell intrinsic and extrinsic factors. We found that transcripts of G0/G1 switch gene 2 (G0S2) are enriched in lineage− Sca-1+ c-kit+ (LSK) CD150+ CD48− CD41− cells, a population highly enriched for quiescent HSCs, whereas G0S2 expression is suppressed in dividing LSK CD150+ CD48− cells. Gain-of-function analyses using retroviral expression vectors in bone marrow cells showed that G0S2 localizes to the mitochondria, endoplasmic reticulum, and early endosomes in hematopoietic cells. Co-transplantation of bone marrow cells transduced with the control or G0S2 retrovirus led to increased chimerism of G0S2-overexpressing cells in femurs, although their contribution to the blood was reduced. This finding was correlated with increased quiescence in G0S2-overexpressing HSCs (LSK CD150+ CD48−) and progenitor cells (LS−K). Conversely, silencing of endogenous G0S2 expression in bone marrow cells increased blood chimerism upon transplantation and promoted HSC cell division, supporting an inhibitory role for G0S2 in HSC proliferation. A proteomic study revealed that the hydrophobic domain of G0S2 interacts with a domain of nucleolin that is rich in arginine-glycine-glycine repeats, which results in the retention of nucleolin in the cytosol. We showed that this cytosolic retention of nucleolin occurs in resting, but not proliferating, wild-type LSK CD150+ CD48− cells. Collectively, we propose a novel model of HSC quiescence in which elevated G0S2 expression can sequester nucleolin in the cytosol, precluding its pro-proliferation functions in the nucleolus.

Evaluation of intramitochondrial ATP levels identifies G0/G1 switch gene 2 as a positive regulator of oxidative phosphorylation

“…A limited number of studies have implied that G0s2 is involved in cell proliferation (33), differentiation (19), apoptosis (34), inflammation (35), and lipid metabolism (36) in various cellular settings. Moreover, G0s2 was reported to localize to the cytosol (33), endoplasmic reticulum (19), mitochondria (34), or the surface of lipid droplets (36).…”

Mice lacking G0S2 are lean and cold-tolerant

“…7 In hematopoietic progenitor cells as well as in human APL cell line, G0S2 was also found to bind to nucleolin, which is known to be involved in rRNA synthesis, chromatin remodeling and cell proliferation. 5,27,28 This binding results in the cytoplasmic retention of nucleolin and decreased proliferation of these cells. 5,27 Given accumulating evidence for G0S2 as a potential tumor suppressor, we are planning to examine the in vivo effect of G0S2 loss on tumorigenesis.…”

“…5,27,28 This binding results in the cytoplasmic retention of nucleolin and decreased proliferation of these cells. 5,27 Given accumulating evidence for G0S2 as a potential tumor suppressor, we are planning to examine the in vivo effect of G0S2 loss on tumorigenesis.…”

“…G0S2 is abundantly expressed in adipose tissue, and is also expressed in other tissues such as liver and hematopoietic cells. [2][3][4][5] When acute promyelocytic leukemia (APL) cells were treated with all-trans retinoic acid to induce differentiation and reduce tumorigenicity, G0S2 levels were markedly induced. 6 Transcriptional regulation of G0S2 is cell context-dependent.…”

G0/G1 switch gene-2 regulates human adipocyte lipolysis by affecting activity and localization of adipose triglyceride lipase

“…This protein was initially identifi ed in 1991 to be transiently expressed in lymphocytes during the switch from the G0 to the G1 phase of the cell cycle ( 14 ). A very recent study reported that G0S2 interacts with nucleolin, resulting in its cytosolic retention and thereby leading to reduced proliferation of hematopoetic stem cells ( 15 ). The role of G0S2 in the cell cycle remains unknown, but the protein was shown to be involved in apoptosis ( 16 ).…”