The RNA-binding Protein Landscapes Differ Between Mammalian Organs and Cultured Cells

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Apr 12

PMID 37045843

Authors

Joel I Perez-Perri

Dunja Ferring-Appel

Ina Huppertz

Thomas Schwarzl

Sudeep Sahadevan

Frank Stein

Mandy Rettel

Bruno Galy

Matthias W Hentze

Affiliations

Soon will be listed here.

Abstract

System-wide approaches have unveiled an unexpected breadth of the RNA-bound proteomes of cultured cells. Corresponding information regarding RNA-binding proteins (RBPs) of mammalian organs is still missing, largely due to technical challenges. Here, we describe ex vivo enhanced RNA interactome capture (eRIC) to characterize the RNA-bound proteomes of three different mouse organs. The resulting organ atlases encompass more than 1300 RBPs active in brain, kidney or liver. Nearly a quarter (291) of these had formerly not been identified in cultured cells, with more than 100 being metabolic enzymes. Remarkably, RBP activity differs between organs independent of RBP abundance, suggesting organ-specific levels of control. Similarly, we identify systematic differences in RNA binding between animal organs and cultured cells. The pervasive RNA binding of enzymes of intermediary metabolism in organs points to tightly knit connections between gene expression and metabolism, and displays a particular enrichment for enzymes that use nucleotide cofactors. We describe a generically applicable refinement of the eRIC technology and provide an instructive resource of RBPs active in intact mammalian organs, including the brain.

Citing Articles

Regulation of gene expression through protein-metabolite interactions.

Hornisch M, Piazza I NPJ Metab Health Dis. 2025; 3(1):7.

PMID: 40052108 PMC: 11879850. DOI: 10.1038/s44324-024-00047-w.

Host RNA-Binding Proteins as Regulators of HIV-1 Replication.

Giraldo-Ocampo S, Valiente-Echeverria F, Soto-Rifo R Viruses. 2025; 17(1).

PMID: 39861832 PMC: 11768693. DOI: 10.3390/v17010043.

The impact of IDR phosphorylation on the RNA binding profiles of proteins.

Modic M, Adamek M, Ule J Trends Genet. 2024; 40(7):580-586.

PMID: 38705823 PMC: 7616821. DOI: 10.1016/j.tig.2024.04.004.

Cytosolic RNA binding of the mitochondrial TCA cycle enzyme malate dehydrogenase.

Noble M, Chatterjee A, Sekaran T, Schwarzl T, Hentze M RNA. 2024; 30(7):839-853.

PMID: 38609156 PMC: 11182015. DOI: 10.1261/rna.079925.123.

Interrogation of RNA-protein interaction dynamics in bacterial growth.

Monti M, Herman R, Mancini L, Capitanchik C, Davey K, Dawson C Mol Syst Biol. 2024; 20(5):573-589.

PMID: 38531971 PMC: 11066096. DOI: 10.1038/s44320-024-00031-y.

References

Van Nostrand E, Pratt G, Shishkin A, Gelboin-Burkhart C, Fang M, Sundararaman B . Robust transcriptome-wide discovery of RNA-binding protein binding sites with enhanced CLIP (eCLIP). Nat Methods. 2016; 13(6):508-14. PMC: 4887338. DOI: 10.1038/nmeth.3810. View

Cox J, Mann M . MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol. 2008; 26(12):1367-72. DOI: 10.1038/nbt.1511. View

Na Y, Kim H, Choi Y, Shin S, Jung J, Kwon S . FAX-RIC enables robust profiling of dynamic RNP complex formation in multicellular organisms in vivo. Nucleic Acids Res. 2020; 49(5):e28. PMC: 7968992. DOI: 10.1093/nar/gkaa1194. View

Constable A, Quick S, Gray N, Hentze M . Modulation of the RNA-binding activity of a regulatory protein by iron in vitro: switching between enzymatic and genetic function?. Proc Natl Acad Sci U S A. 1992; 89(10):4554-8. PMC: 49121. DOI: 10.1073/pnas.89.10.4554. View

Chang C, Curtis J, Maggi Jr L, Faubert B, Villarino A, OSullivan D . Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell. 2013; 153(6):1239-51. PMC: 3804311. DOI: 10.1016/j.cell.2013.05.016. View

Zhou F, Lu Y, Ficarro S, Adelmant G, Jiang W, Luckey C . Genome-scale proteome quantification by DEEP SEQ mass spectrometry. Nat Commun. 2013; 4:2171. PMC: 3770533. DOI: 10.1038/ncomms3171. View

Liao Y, Castello A, Fischer B, Leicht S, Foehr S, Frese C . The Cardiomyocyte RNA-Binding Proteome: Links to Intermediary Metabolism and Heart Disease. Cell Rep. 2016; 16(5):1456-1469. PMC: 4977271. DOI: 10.1016/j.celrep.2016.06.084. View

Franken H, Mathieson T, Childs D, Sweetman G, Werner T, Togel I . Thermal proteome profiling for unbiased identification of direct and indirect drug targets using multiplexed quantitative mass spectrometry. Nat Protoc. 2015; 10(10):1567-93. DOI: 10.1038/nprot.2015.101. View

Gebauer F, Schwarzl T, Valcarcel J, Hentze M . RNA-binding proteins in human genetic disease. Nat Rev Genet. 2020; 22(3):185-198. DOI: 10.1038/s41576-020-00302-y. View

10.

Treiber T, Treiber N, Plessmann U, Harlander S, Daiss J, Eichner N . A Compendium of RNA-Binding Proteins that Regulate MicroRNA Biogenesis. Mol Cell. 2017; 66(2):270-284.e13. DOI: 10.1016/j.molcel.2017.03.014. View

11.

Castello A, Fischer B, Frese C, Horos R, Alleaume A, Foehr S . Comprehensive Identification of RNA-Binding Domains in Human Cells. Mol Cell. 2016; 63(4):696-710. PMC: 5003815. DOI: 10.1016/j.molcel.2016.06.029. View

12.

Sysoev V, Fischer B, Frese C, Gupta I, Krijgsveld J, Hentze M . Global changes of the RNA-bound proteome during the maternal-to-zygotic transition in Drosophila. Nat Commun. 2016; 7:12128. PMC: 4935972. DOI: 10.1038/ncomms12128. View

13.

Matia-Gonzalez A, Laing E, Gerber A . Conserved mRNA-binding proteomes in eukaryotic organisms. Nat Struct Mol Biol. 2015; 22(12):1027-33. PMC: 5759928. DOI: 10.1038/nsmb.3128. View

14.

Schieweck R, Ninkovic J, Kiebler M . RNA-binding proteins balance brain function in health and disease. Physiol Rev. 2020; 101(3):1309-1370. DOI: 10.1152/physrev.00047.2019. View

15.

Trendel J, Schwarzl T, Horos R, Prakash A, Bateman A, Hentze M . The Human RNA-Binding Proteome and Its Dynamics during Translational Arrest. Cell. 2018; 176(1-2):391-403.e19. DOI: 10.1016/j.cell.2018.11.004. View

16.

Perez-Perri J, Rogell B, Schwarzl T, Stein F, Zhou Y, Rettel M . Discovery of RNA-binding proteins and characterization of their dynamic responses by enhanced RNA interactome capture. Nat Commun. 2018; 9(1):4408. PMC: 6199288. DOI: 10.1038/s41467-018-06557-8. View

17.

Huppertz I, Perez-Perri J, Mantas P, Sekaran T, Schwarzl T, Russo F . Riboregulation of Enolase 1 activity controls glycolysis and embryonic stem cell differentiation. Mol Cell. 2022; 82(14):2666-2680.e11. DOI: 10.1016/j.molcel.2022.05.019. View

18.

Carbon S, Ireland A, Mungall C, Shu S, Marshall B, Lewis S . AmiGO: online access to ontology and annotation data. Bioinformatics. 2008; 25(2):288-9. PMC: 2639003. DOI: 10.1093/bioinformatics/btn615. View

19.

Perez-Perri J, Noerenberg M, Kamel W, Lenz C, Mohammed S, Hentze M . Global analysis of RNA-binding protein dynamics by comparative and enhanced RNA interactome capture. Nat Protoc. 2020; 16(1):27-60. PMC: 7116560. DOI: 10.1038/s41596-020-00404-1. View

20.

Kwon S, Yi H, Eichelbaum K, Fohr S, Fischer B, You K . The RNA-binding protein repertoire of embryonic stem cells. Nat Struct Mol Biol. 2013; 20(9):1122-30. DOI: 10.1038/nsmb.2638. View