Otto Warburg Medal
From Otto Warburg to Riboregulation: a 100 year journey in metabolism

Matthias Hentze

European Molecular Biology Laboratory (EMBL), Heidelberg

RBPs) enjoy almost half a century of emerging recognition for their widespread functions in posttranscriptional gene regulation. Thanks to Otto Warburg and his colleagues, metabolic enzymes and pathways have been researched over a 100 year journey, and the paths of metabolic enzymes and RBPs have rarely crossed. Iron regulatory protein 1 (IRP1, formerly IRE-BP), identical with cytosolic aconitase (ACO1) was an early and notable exception (Constable et al., 1992).
Following the discovery that the RNA-binding proteome is far larger than previously anticipated (Castello et al., 2012; Hentze et al., 2018), riboregulation, the direct control of protein function by RNA, has begun to emerge as a new paradigm of biological control (Horos et al., 2019; Huppertz et al., 2022; Chatterjee et al., 2024) that adds a surprising twist to our understanding of metabolic enzymes and metabolism. We are beginning to understand molecular mechanisms of riboregulation, and I will discuss their implications for metabolism, cell biology and disease mechanisms as well as the arising new therapeutic opportunities.

Constable, A., S. Quick, N.K. Gray and M.W. Hentze. Modulation of the RNA-binding activity of a regulatory protein [IRE-BP] by iron in vitro: switching between enzymatic and genetic function? Proc. Natl. Acad. Sci. U.S.A. 89, 4554-4558, 1992.

Castello, A., B. Fischer, K. Schuschke, R. Horos, B.M. Beckmann, C. Strein, N.E. Davey, D.T. Humphreys, T. Preiss, L.M. Steinmetz, J. Krijgsveld and M.W. Hentze. Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 149, 1393-1406, 2012.

Hentze, M.W., A. Castello, T. Schwarzl and T. Preiss, A brave new world of RNA-binding proteins. Nature Rev. Mol. Cell Biol. 19, 327-341, 2018.

Horos, R., M. Büscher, R. Kleinendorst, A.-M. Alleaume, A.K. Tarafder, T. Schwarzl, D. Dziuba, C. Tischer, E.M. Zielonka, A. Adak, A. Castello, W. Huber, C. Sachse and M.W. Hentze, The small non-coding vault RNA1-1 acts as a riboregulator of autophagy. Cell 176, 1054-1067, 2019.

Huppertz, I., J.I. Perez-Perri, P. Mantas, T. Sekaran, T. Schwarzl, F. Russo, D. Ferring-Appel, L. Dimitrova-Paternoga, E. Kafkia, J. Hennig, P.A. Neveu, K. Patil and M.W. Hentze. Riboregulation of Enolase 1 Activity Controls Glycolysis and Embryonic Stem Cell Differentiation. Mol. Cell 82, 2666-2680, 2022.

Chatterjee, A., M. Noble, T. Sekaran, V. Ravi, D. Ferring-Appel, T. Schwarzl, R. Rampelt and M.W. Hentze. RNA promotes mitochondrial import of F1-ATP synthase subunit alpha (ATP5A1). doi: https://doi.org/10.1101/2024.08.19.608659.

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