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Publications

Journal Article Ppublish

PubMed: 40739340 DOI: 10.1038/s41556-025-01711-z

PEX39 facilitates the peroxisomal import of PTS2-containing proteins.

Nat Cell Biol 27(8):1256-1271

Authors: Walter W Chen, Tony A Rodrigues, Daniel Wendscheck, Ana G Pedrosa, Chendong Yang, Tânia Francisco, Till Möcklinghoff, Alexandros Zografakis, Bernardo Nunes-Silva, Reut E Avraham, Ana R Silva, Maria J Ferreira, Hirak Das, Janet Koster, Simone Neuwirth, Julian Bender, Silke Oeljeklaus, Varun Sondhi, Christos Gatsogiannis, Maya Schuldiner, Einat Zalckvar, Kay Hofmann, Hans R Waterham, Ralph J DeBerardinis, Jorge E Azevedo, Bettina Warscheid

Affiliations

  • Division of Neonatal-Perinatal Medicine, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.
  • Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
  • Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.
  • Biochemistry II, Theodor-Boveri-Institute, Biocenter and Faculty of Chemistry and Pharmacy, University of Würzburg, Würzburg, Germany.
  • Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Biochemistry and Functional Proteomics, Institute of Biology II, Faculty of Biology, University of Freiburg, Freiburg, Germany.
  • German Cancer Research Center, Systems Biology of Signal Transduction, Heidelberg, Germany.
  • Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
  • Laboratory Genetic Metabolic Diseases, Amsterdam UMC-location AMC, University of Amsterdam, Amsterdam, the Netherlands.
  • Institute of Medical Physics and Biophysics, University of Münster, Münster, Germany.
  • Center for Soft Nanoscience, University of Münster, Münster, Germany.
  • Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
  • Institute for Genetics, University of Cologne, Cologne, Germany.
  • Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands.
  • Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.
  • Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
  • Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.
  • Biochemistry II, Theodor-Boveri-Institute, Biocenter and Faculty of Chemistry and Pharmacy, University of Würzburg, Würzburg, Germany.
  • Biochemistry and Functional Proteomics, Institute of Biology II, Faculty of Biology, University of Freiburg, Freiburg, Germany.

Abstract

Peroxisomes are metabolic organelles essential for human health. Defects in peroxisomal biogenesis proteins (also known as peroxins (PEXs)) cause devastating disease. PEX7 binds proteins containing a type 2 peroxisomal targeting signal (PTS2) to enable their import from the cytosol into peroxisomes, although many aspects of this process remain enigmatic. Utilizing in vitro assays, yeast and human cells, we show that PEX39, a previously uncharacterized protein, is a cytosolic peroxin that facilitates the import of PTS2-containing proteins by binding PEX7 and stabilizing its interaction with cargo proteins containing a PTS2. PEX39 and PEX13, a peroxisomal membrane translocon protein, both possess an (R/K)PWE motif necessary for PEX7 binding. Handover of PEX7 from PEX39 to PEX13 via these motifs provides a new paradigm for peroxisomal protein import and biogenesis. Collectively, this work reveals how PEX39 and (R/K)PWE motifs facilitate the import of PTS2-containing proteins and advances our understanding of peroxisomal disease.

MeSH

Cytosol, Peroxins, Organelle Biogenesis, Cell Biology