PEX39 facilitates the peroxisomal import of PTS2-containing proteins PMID: 40739340

GLP-1 and Obesity Research

2026-08-18

PEX39 facilitates the peroxisomal import of PTS2-containing proteins

Nat Cell Biol. 2025 Aug;27(8):1256-1271. doi: 10.1038/s41556-025-01711-z.

Walter W Chen ^# ¹ ² , Tony A Rodrigues ^# ³ ⁴ ⁵ , Daniel Wendscheck ^# ⁶ , Ana G Pedrosa ³ ⁴ ⁵ , Chendong Yang ⁷ , Tânia Francisco ³ ⁴ ⁵ , Till Möcklinghoff ⁸ ⁹ , Alexandros Zografakis ⁶ ⁸ , Bernardo Nunes-Silva ³ , Reut E Avraham ¹⁰ , Ana R Silva ³ ⁴ ⁵ , Maria J Ferreira ³ ⁴ ⁵ , Hirak Das ⁶ , Janet Koster ¹¹ , Simone Neuwirth ¹² ¹³ , Julian Bender ⁶ , Silke Oeljeklaus ⁶ , Varun Sondhi ⁷ ¹⁴ , Christos Gatsogiannis ¹² ¹³ , Maya Schuldiner ¹⁰ , Einat Zalckvar ¹⁰ ¹⁵ , Kay Hofmann ¹⁶ , Hans R Waterham ¹¹ ¹⁷ , Ralph J DeBerardinis ¹⁸ ¹⁹ ²⁰ , Jorge E Azevedo ²¹ ²² ²³ , Bettina Warscheid ²⁴ ²⁵

Affiliations

1. Division of Neonatal-Perinatal Medicine, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected].
2. Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected].
3. Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.
4. Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
5. Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.
6. Biochemistry II, Theodor-Boveri-Institute, Biocenter and Faculty of Chemistry and Pharmacy, University of Würzburg, Würzburg, Germany.
7. Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
8. Biochemistry and Functional Proteomics, Institute of Biology II, Faculty of Biology, University of Freiburg, Freiburg, Germany.
9. German Cancer Research Center, Systems Biology of Signal Transduction, Heidelberg, Germany.
10. Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
11. Laboratory Genetic Metabolic Diseases, Amsterdam UMC-location AMC, University of Amsterdam, Amsterdam, the Netherlands.
12. Institute of Medical Physics and Biophysics, University of Münster, Münster, Germany.
13. Center for Soft Nanoscience, University of Münster, Münster, Germany.
14. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
15. The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
16. Institute for Genetics, University of Cologne, Cologne, Germany.
17. Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands.
18. Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected].
19. Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected].
20. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected].
21. Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal. [email protected].
22. Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal. [email protected].
23. Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal. [email protected].
24. Biochemistry II, Theodor-Boveri-Institute, Biocenter and Faculty of Chemistry and Pharmacy, University of Würzburg, Würzburg, Germany. [email protected].
25. Biochemistry and Functional Proteomics, Institute of Biology II, Faculty of Biology, University of Freiburg, Freiburg, Germany. [email protected].
# Contributed equally.

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.