TY - JOUR
T1 - PEX39 facilitates the peroxisomal import of PTS2-containing proteins
AU - Chen, Walter W.
AU - Rodrigues, Tony A.
AU - Wendscheck, Daniel
AU - Pedrosa, Ana G.
AU - Yang, Chendong
AU - Francisco, Tânia
AU - Möcklinghoff, Till
AU - Zografakis, Alexandros
AU - Nunes-Silva, Bernardo
AU - Avraham, Reut E.
AU - Silva, Ana R.
AU - Ferreira, Maria J.
AU - Das, Hirak
AU - Koster, Janet
AU - Neuwirth, Simone
AU - Bender, Julian
AU - Oeljeklaus, Silke
AU - Sondhi, Varun
AU - Gatsogiannis, Christos
AU - Schuldiner, Maya
AU - Zalckvar, Einat
AU - Hofmann, Kay
AU - Waterham, Hans R.
AU - DeBerardinis, Ralph J.
AU - Azevedo, Jorge E.
AU - Warscheid, Bettina
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/8
Y1 - 2025/8
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105012304484
U2 - 10.1038/s41556-025-01711-z
DO - 10.1038/s41556-025-01711-z
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C2 - 40739340
AN - SCOPUS:105012304484
SN - 1465-7392
VL - 27
SP - 1256
EP - 1271
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 8
ER -
