V happy to share my work in @RJDLab @CRI_UTSW from past 2 yr! In equal collab with Tony Rodrigues, @dwendscheck, Jorge Azevedo’s lab, @warscheidlab, we have discovered PEX39, the first human peroxisomal biogenesis protein (peroxin/PEX) found in > 20 yr! 🧵biorxiv.org/content/10.110…
Peroxisomes are metabolic organelles essential for human health. Peroxin defects can cause severe disease as early as neonatal period. PEX7 binds newly made enzymes containing a type 2 peroxisomal targeting signal (PTS2) to enable their import from the cytosol into peroxisomes.
We identified PEX39 by studying previously uncharacterized proteins in yeast (Yjr012c) and humans (C6ORF226) and found that these proteins facilitate import of PTS2 proteins by binding to PEX7 and stabilizing its interaction with the cargo protein.
We identify an impt, conserved [R/K]PWE motif in PEX39 and PEX13, a transmembrane peroxin thought to form conduit by which PTS2 proteins enter peroxisomes. [R/K]PWE is necessary for sequential binding of PEX7 by PEX39 in the cytosol and then by PEX13 at the peroxisomal membrane.
The sequential engagement of PEX7 by [R/K]PWE-containing peroxins represents a new paradigm in peroxisomal protein import and biogenesis.
Surprisingly, both loss and overexpression of PEX39 impairs PTS2-protein import, which implies that PEX39 dosage needs to be tightly controlled to maximize PTS2-protein import, a unique phenomenon amongst cytosolic peroxins.
Still lots to uncover about PEX39, ranging from structural studies to mouse models and human genetics but we look forward to the future directions!
Big thanks to my wife @hoiseetsao and my mentor @RJDLab for their amazing support, as well as to Chendong Yang, Ana Pedrosa, Einat Zalckvar, Maya Schuldiner, @LabHofmann, Hans Waterham, and other authors, including @aretaon @tmoecklinghoff @hirak_das13.
Lastly, this work underscores the great value of interactomes like BioPlex (@jwadeharperlab @GygiLab @EdHuttlin) for finding new biology. TY to @jwadeharperlab in whose lab I first came across C6ORF226 in BioPlex.
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