PEX39促进含PTS2蛋白的过氧化物酶体导入。

PEX39 facilitates the peroxisomal import of PTS2-containing proteins.

作者信息

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

机构信息

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.

出版信息

Nat Cell Biol. 2025 Jul 30. doi: 10.1038/s41556-025-01711-z.

DOI:10.1038/s41556-025-01711-z

PMID:40739340

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.

摘要

过氧化物酶体是对人类健康至关重要的代谢细胞器。过氧化物酶体生物发生蛋白（也称为过氧化物酶（PEXs））的缺陷会导致严重疾病。PEX7结合含有2型过氧化物酶体靶向信号（PTS2）的蛋白质，使其能够从细胞质导入过氧化物酶体，尽管这一过程的许多方面仍然未知。利用体外试验、酵母和人类细胞，我们发现PEX39（一种先前未被鉴定的蛋白质）是一种细胞质过氧化物酶，它通过结合PEX7并稳定其与含有PTS2的货物蛋白的相互作用，促进含PTS2蛋白质的导入。PEX39和过氧化物酶体膜转运蛋白PEX13都具有PEX7结合所需的（R/K）PWE基序。通过这些基序将PEX7从PEX39传递给PEX13为过氧化物酶体蛋白导入和生物发生提供了一个新的范例。总的来说，这项工作揭示了PEX39和（R/K）PWE基序如何促进含PTS2蛋白质的导入，并增进了我们对过氧化物酶体疾病的理解。