Diurnal control of iron responsive element containing mRNAs through iron regulatory proteins IRP1 and IRP2 is mediated by feeding rhythms

Abstract

A central mechanism for cellular iron homeostasis involves iron regulatory proteins, IRP1 and IRP2, that interact with iron regulatory elements (IREs) on mRNAs. IRPs act as sensors of metabolic cues (foremost of iron itself) and can regulate either translation or transcript stability, depending on IRE location within the mRNA. In liver, IRP2 is widely considered the principle player mediating IRE regulation. Here, we uncover high-amplitude diurnal rhythms in the regulation of several prominent IRE-containing mRNAs in liver, compatible with maximal IRP activity at the onset of the dark phase of the day (a timepoint likely underrepresented in previous studies on IRP/IRE regulation). We find that IRP2 protein abundance itself oscillates over the day, yet ribosome profiling in livers from IRP2-deficient mice uncovers that IRP2 is dispensable for maximal repression of its rhythmically regulated target mRNAs at the time of its highest abundance, i.e. the light-dark transition. These findings are compatible with temporally controlled redundancy in IRP activities, with IRP2 exclusively mediating regulation of IRE-containing transcripts in the light phase and redundancy, conceivably with IRP1, at dark onset. We further unveil that the identified diurnal IRP/IRE regulation can ensue in the absence of a functional circadian clock as long as feeding is rhythmic, and that it follows feeding rhythms also in the presence of a clock, thus identifying feeding-associated signals as the dominant driver of IRP/IRE rhythmicity. Altogether, our study identifies a novel level of regulatory control and complexity in a metabolic pathway that had been considered well-understood since a long time.

Diurnal control of iron responsive element containing mRNAs through iron regulatory proteins IRP1 and IRP2 is mediated by feeding rhythms

“…All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Files. Sequencing data produced in the framework of this study have been deposited at GEO (GSE243134) [75]. Liver and kidney Ribo-seq and RNA-seq data for Fig.…”