Protein phosphatase 2A inhibitor modulates natural killer cell homeostasis in peripheral tissues

Yui Shinzawa; So-Ichiro Sasaki; Sadahiro Iwabuchi; Shinichi Hashimoto; Manabu Kawada; Yoshihiro Hayakawa

doi:10.1016/j.bbrc.2024.151020

Protein phosphatase 2A inhibitor modulates natural killer cell homeostasis in peripheral tissues

Biochem Biophys Res Commun. 2024 Nov 19:741:151020. doi: 10.1016/j.bbrc.2024.151020. Online ahead of print.

Authors

Yui Shinzawa¹, So-Ichiro Sasaki², Sadahiro Iwabuchi³, Shinichi Hashimoto⁴, Manabu Kawada⁵, Yoshihiro Hayakawa⁶

Affiliations

¹ Section of Host Defences, Institute of Natural Medicine, University of Toyama, 2630, Sugitani, Toyama-shi, Toyama 930-0194, Japan. Electronic address: d2262308@ems.u-toyama.ac.jp.
² Section of Host Defences, Institute of Natural Medicine, University of Toyama, 2630, Sugitani, Toyama-shi, Toyama 930-0194, Japan. Electronic address: sasaki@inm.u-toyama.ac.jp.
³ Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama-shi, Wakayama 641-8509, Japan. Electronic address: iwabuchi@wakayama-med.ac.jp.
⁴ Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama-shi, Wakayama 641-8509, Japan.
⁵ Laboratory of Oncology, Institute of Microbial Chemistry, 3-14-23, Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan. Electronic address: kawadam@bikaken.or.jp.
⁶ Section of Host Defences, Institute of Natural Medicine, University of Toyama, 2630, Sugitani, Toyama-shi, Toyama 930-0194, Japan. Electronic address: haya@inm.u-toyama.ac.jp.

PMID: 39577078
DOI: 10.1016/j.bbrc.2024.151020

Abstract

Although natural killer (NK) cell responses to tumor and viral infection have been studied, the mechanisms underlying NK cell homeostasis in vivo remain unclear. In this study, we demonstrate the pharmacological action of cytostatin, a protein phosphatase 2A (PP2A) specific inhibitor (PP2Ai), on NK cells in regulating NK cell homeostasis in the peripheral tissues. We found that PP2Ai treatment decreased NK cell percentages in the bone marrow and secondary lymphoid tissues while increasing NK cell percentages in peripheral tissues such as the lung and liver. In the peripheral tissues of PP2Ai-treated mice, Ki-67 expression and BrdU uptake in NK cells were upregulated, and an initial increase in the pre-mature CD11b^hiCD27^hi NK subset was observed, followed by an increase in the terminally differentiated mature CD11b^hiCD27^lo NK subset. In addition, bone marrow Ki-67⁺ NK cells predominantly expressed CX3CR1 in the PP2Ai-treated mice and were further mobilized to the peripheral tissues. Among various target molecules of PP2A, we found that the upregulation of c-Myc pathway and its phosphorylation, along with its downstream cyclin E expression and G1/S cell cycle transition in PP2Ai-treated mice NK cells. Our results suggest that PP2Ai modulates NK cell proliferation through c-Myc and cyclin E, leading to their maturation and trafficking from the bone marrow to the peripheral tissues.

Keywords: Homeostasis; NK cell; PP2A; Proliferation; c-Myc.