Do transcription factor-based receptors moonlight as enzymes?

Overview & Synopsis

How cells and organelles communicate is a fundamental question in biology. Proteins can exhibit moonlighting function in different organelles and receptors can also exhibit duality in sensing.1,2 Likewise, several transcription factors can act as receptors and major examples include retinoic acid, vitamin D and estrogen receptors.3–5 But then a question arises, can transcription factors (without any explicit domains for catalytic activity) can also act as enzymes? For instance, let’s consider heme-binding transcription factors such as bacterial CooA, Drosophila E75, mammalian REV-ERBb and NPAS2, all of which can act as gasoreceptors.6–9 These transcription factors bind and sense gas (solute) such as carbon monoxide or nitric oxide primarily via heme. But then what stops these transcription factors from acting as enzymes via the heme group? If it is all about the local microenvironment of the amino acid residues near the heme, how stable are these microenvironment when these transcription factors can bind various factors or face varying environmental conditions in a cell which the transcription factors must traverse or gets localized into?10 Will such local cellular environment-induced changes or binding partners can enable a switch of these transcription factors to act as enzymes? As gasoreceptors are likely also to be other than hemoproteins, addressing this question will be essential to understand some of the complexities of gasocrine signaling. REFERENCES 1. Boukouris AE, Zervopoulos SD, Michelakis ED. Metabolic Enzymes Moonlighting in the Nucleus: Metabolic Regulation of Gene Transcription. Trends Biochem Sci 2016; 41:712–30. 2. Anbalagan S. Sugar-sensing swodkoreceptors and swodkocrine signaling. Animal Model Exp Med 2025; 3. Aono S. Gas Sensing in Cells. Royal Society of Chemistry; 2017. 4. Anbalagan S. Gas-sensing riboceptors. RNA Biol 2024; 21:1–6. 5. Thornton JW, Need E, Crews D. Resurrecting the Ancestral Steroid Receptor: Ancient Origin of Estrogen Signaling. Science 2003; 301:1714–7. 6. Shelver D, Kerby RL, He Y, Roberts GP. CooA, a CO-sensing transcription factor from Rhodospirillum rubrum, is a CO-binding heme protein. Proceedings of the National Academy of Sciences 1997; 94:11216–20. 7. Reinking J, Lam MMS, Pardee K, Sampson HM, Liu S, Yang P, Williams S, White W, Lajoie G, Edwards A, et al. The Drosophila Nuclear Receptor E75 Contains Heme and Is Gas Responsive. Cell 2005; 122:195–207. 8. Pardee KI, Xu X, Reinking J, Schuetz A, Dong A, Liu S, Zhang R, Tiefenbach J, Lajoie G, Plotnikov AN, et al. The structural basis of gas-responsive transcription by the human nuclear hormone receptor REV-ERBbeta. PLoS Biol 2009; 7:e43. 9. Dioum EM, Rutter J, Tuckerman JR, Gonzalez G, Gilles-Gonzalez M-A, McKnight SL. NPAS2: a gas-responsive transcription factor. Science 2002; 298:2385–7. 10. Tsai A-L, Martin E, Berka V, Olson JS. How do heme-protein sensors exclude oxygen? Lessons learned from cytochrome c’, Nostoc puntiforme heme nitric oxide/oxygen-binding domain, and soluble guanylyl cyclase. Antioxid Redox Signal 2012; 17:1246–63.