The PAS-B Domain of BMAL1 Controls Proliferation, Cellular Energetics, and Inflammatory Response in Human Monocytic Cell Line THP-1

TL;DR

This study shows that the BMAL1-PAS-B domain regulates cell growth, energy use, and inflammation in THP-1 cells, possibly through glycolysis control.

Contribution

The BMAL1-PAS-B domain is identified as a novel regulator of monocyte function through its control of glycolytic activity.

Findings

THP-1 cells lacking the BMAL1-PAS-B domain show disrupted circadian gene expression and reduced proliferation and energy metabolism.

THP-1#207 cells produce less IL-1β and more IL-10 in response to LPS compared to THP-1 cells.

2-DG treatment mimics the metabolic and inflammatory phenotypes of BMAL1-PAS-B-deficient cells.

Abstract

Brain muscle ARNT-like1 (Bmal1) is a transcriptional factor, consisting of basic helix–loop–helix (bHLH) and PER-ARNT-SIM (PAS) domains, that plays a central role in circadian clock activity. However, the precise roles of the BMAL1-PAS domain, a circadian rhythm-regulating structure, remain unexplored in monocytes. Here, we highlight the BMAL1-PAS domain as a key structure in monocyte pleiotropic functions by using human monocytic cell line THP-1. THP-1 cells lacking the BMAL1-PAS-B domain (THP-1#207) abrogated the circadian expression of core clock genes. THP-1#207 cells exhibited less proliferation, glycolysis and oxidative phosphorylation activity, and LPS-induced IL-1β production, but exhibited more production of LPS-induced IL-10 than THP-1 cells. A quantitative proteomics analysis revealed significant expression changes in ~10% metabolic enzymes in THP-1#207 cells compared to THP-1 cells, including reduction in a rate-limiting enzyme hexokinase2 (HK2) in the glycolytic pathway. Importantly, treatment of THP-1 with 2-deoxy-D-glucose (2-DG), an HK2 inhibitor, largely recapitulated the phenotypes of THP-1#207 cells. These findings suggest that the BMAL1-PAS-B domain is an important structure for the regulation of proliferation, cellular energetics, and inflammatory response in THP-1 cells, at least in part, via the control of glycolytic activity. Thus, the BMAL1-PAS-B domain may become a promising pharmacological target to control inflammation.

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