Role of the Circadian Gas-Responsive Hemeprotein NPAS2 in Physiology and Pathology
by
, , ,
Emanuele Murgo
1,†,
Tommaso Colangelo
2,3,†
,
Maria Marina Bellet
4,
Francesco Malatesta
5,* and
Gianluigi Mazzoccoli
1,*
1
Department of Medical Sciences, Division of Internal Medicine and Chronobiology Laboratory, Fondazione IRCCS “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy
2
Department of Medical and Surgical Sciences, University of Foggia, Viale Pinto 1, 71100 Foggia, Italy
3
Cancer Cell Signaling Unit, Fondazione IRCCS “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy
4
Department of Medicine and Surgery, University of Perugia, P.le L. Severi 1, 06132 Perugia, Italy
5
Department of Biochemical Sciences “Alessandro Rossi Fanelli”, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Biology 2023, 12(10), 1354; https://doi.org/10.3390/biology12101354
Submission received: 22 August 2023
/
Revised: 14 October 2023
/
Accepted: 20 October 2023
/
Published: 22 October 2023
(This article belongs to the Special Issue Biological Rhythms and Molecular Clockworks in Physiology and Pathology)
Simple Summary
NPAS2, short for Neuronal PAS Domain Protein 2, is a transcription factor involved in regulating the circadian rhythms and sleep–wake cycles in mammals, including humans. It is a key component of the molecular clockwork that governs daily biological processes. NPAS2 binds heme as a prosthetic group and CO at micromolar concentrations, with ensuing changes in DNA affinity. In this way, gaseous signaling plus heme-based sensing and redox balance modify NPAS2 transcriptional activity and the expression of target genes. NPAS2 plays a crucial role in metabolism regulation and in maintaining the body’s internal clock synchronized with the day–night cycle. Dysregulation of NPAS2 can lead to disruptions in circadian rhythms and may contribute to sleep disturbances, psychiatric disorders and other health issues, such as neoplastic, cardiovascular and cerebrovascular diseases. Alternatively, NPAS2 could represent a valuable predictive biomarker for prevention/stratification strategies and a promising druggable target for innovative therapeutic approaches.
Abstract
Neuronal PAS domain protein 2 (NPAS2) is a hemeprotein comprising a basic helix–loop–helix domain (bHLH) and two heme-binding sites, the PAS-A and PAS-B domains. This protein acts as a pyridine nucleotide-dependent and gas-responsive CO-dependent transcription factor and is encoded by a gene whose expression fluctuates with circadian rhythmicity. NPAS2 is a core cog of the molecular clockwork and plays a regulatory role on metabolic pathways, is important for the function of the central nervous system in mammals, and is involved in carcinogenesis as well as in normal biological functions and processes, such as cardiovascular function and wound healing. We reviewed the scientific literature addressing the various facets of NPAS2 and framing this gene/protein in several and very different research and clinical fields.
Keywords:
NPAS2; circadian; rhythmicity; molecular clockwork; PAS domain; heme
