2. Academic Validation
  3. Opposing roles of pseudokinases NRBP1 and NRBP2 in regulating L1 retrotransposition

Opposing roles of pseudokinases NRBP1 and NRBP2 in regulating L1 retrotransposition

  • Nat Commun. 2025 Jul 11;16(1):6327. doi: 10.1038/s41467-025-61626-z.
Wei Yang # 1 2,  Shaobo Cong # 1,  Ruoyao Li 1,  Jennifer Schwarz 3 4,  Thilo Schulze 5,  Raban A Gevelhoff 1 6,  Xinyan Chen 1 6,  Sara Ullrich 1,  Kristina Falkenstein 1,  Denis Ott 1,  Pia Eixmann 1,  Angelica Trentino 1,  Antje Thien 1,  Thierry Heidmann 7,  Ekkehard Schulze 1,  Bettina Warscheid 3 8,  Ralf Baumeister 9 10 11 12,  Wenjing Qi 13
Affiliations

Affiliations

  • 1 Bioinformatics and Molecular Genetics, Institute of Biology III, Faculty of Biology, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
  • 2 College of Food Science and Engineering, Shandong Agricultural University, Shandong Engineering Research Center of Food Nutrition and Active Health, Taian, 271018, People's Republic of China.
  • 3 Biochemistry-Functional Proteomics, Institute of Biology II, Faculty of Biology, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
  • 4 European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
  • 5 Department of Animal Evolution and Biodiversity, Georg-August-Universität Göttingen, Untere Karspüle 2, Göttingen, 37073, Germany.
  • 6 Spemann Graduate School of Biology and Medicine (SGBM), Albert-Ludwigs-University Freiburg, Freiburg, 79104, Germany.
  • 7 CNRS UMR 9196, Laboratory of Molecular Physiology and Pathology of Endogenous and Infectious Retroviruses, Gustave Roussy, University Paris-Saclay, Villejuif, France.
  • 8 Biochemistry II, Theodor-Boveri-Institute, Biocenter, University of Würzburg, 97074, Würzburg, Germany.
  • 9 Bioinformatics and Molecular Genetics, Institute of Biology III, Faculty of Biology, Albert-Ludwigs-University Freiburg, Freiburg, Germany. baumeister@celegans.de.
  • 10 Spemann Graduate School of Biology and Medicine (SGBM), Albert-Ludwigs-University Freiburg, Freiburg, 79104, Germany. baumeister@celegans.de.
  • 11 Signalling Research Centers BIOSS and CIBSS, Albert-Ludwigs-University Freiburg, Freiburg, 79104, Germany. baumeister@celegans.de.
  • 12 Center for Biochemistry and Molecular Cell Research, Faculty of Medicine, Albert-Ludwigs-University Freiburg, Freiburg, Germany. baumeister@celegans.de.
  • 13 Bioinformatics and Molecular Genetics, Institute of Biology III, Faculty of Biology, Albert-Ludwigs-University Freiburg, Freiburg, Germany. wenjing.qi@biologie.uni-freiburg.de.
  • # Contributed equally.
PMID: 40645931 DOI: 10.1038/s41467-025-61626-z
Abstract

Gene duplication generates gene paralogs that may undergo diverse fates during evolution, and thus serves as a potent catalyst of biological complexity. Genetic paralogs frequently share redundant functions and may also exhibit antagonistic activities by competing for common interaction partners. Here we show that the gene paralogs NRBP1 and NRBP2 oppositely regulate long interspersed nuclear element-1 (L1) retrotransposition, via influencing integrity of the L1 ribonucleoprotein complex. We demonstrate that the opposing roles of NRBP1 and NRBP2 are not results of a competitive mechanism, but rather due to targeting NRBP1 for degradation by NRBP2, probably through heterodimer formation. Moreover, our phylogenetic analysis shows that the regulatory function of NRBP2 may be acquired later during evolution, suggesting that evolutionary pressure has favored this functional fine-tuning of NRBP1. In summary, our findings not only identify NRBP1/2 as L1 regulators and implicate their involvement in human pathogenesis, but also provide a mechanistic insight into the regulatory details arising from gene duplication.

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