Yagita et al. describe how an integral membrane protein is delivered directly to mammalian peroxisomes instead of passing through the ER.
Peroxisomal membrane proteins can take either a direct or indirect path to their organelle, and both routes are controlled by mammalian cytosolic chaperone PEX19 and its peroxisomal receptor PEX3, or their homologues. The budding yeast protein Pex15, for example, follows an indirect route. Its C-terminal transmembrane domain is first inserted into the ER by an ATPase called Get3, and the protein is then transported to peroxisomes by yeast Pex19 and Pex3. In mammals, PEX19 is also required to deliver PEX26, the orthologue of Pex15, to peroxisomes. But whether PEX26 makes a stopover in the ER was unknown.
Yagita et al. found that PEX19 binds to PEX26 in the cytosol and delivers the protein to peroxisomes by docking onto PEX3. Unlike in yeast, PEX26 didn’t accumulate in the ER of mammalian cells lacking PEX19. Moreover, PEX26 showed no interaction with TRC40, the mammalian homologue of Get3, and still localized to peroxisomes when this ATPase was inhibited.
Mammalian PEX26 therefore takes a different, more direct path to peroxisomes than its budding yeast counterpart. This route is determined by PEX26’s relatively hydrophilic transmembrane domain, which avoids capture by TRC40, and by a stretch of basic residues in PEX26’s C terminus that interact with PEX19. Senior author Yukio Fujiki now wants to investigate how PEX26 is integrated into the peroxisomal membrane after PEX19 and PEX3 have recruited it to the organelle’s surface.
Text by Ben Short