Dually targeted proteins regulate proximity between peroxisomes and partner organelles

Peroxisomes play a central role in fatty acid metabolism. To correctly target to peroxisomes, proteins require specialized targeting signals. One mystery in the field is sorting of proteins that carry both a targeting signal for peroxisomes as well as for other organelles such as mitochondria or the endoplasmic reticulum (ER). Exploring several of these dually localized proteins in Saccharomyces cerevisiae, we observed that they can act as dynamic tethers bridging organelles together through an affinity for organelle-destined targeting factors. We show that this mode of tethering involves the peroxisome import machinery, the ER- mitochondria encounter structure (ERMES) in the case of mitochondria and the GET complex in the case of the ER. Depletion of each of the targeting factors resulted in the accumulation of smaller peroxisomes. We propose that dual targeting of proteins occurs at contact sites and that protein import per se contributes to the maintenance of these membrane proximities. This introduces a previously unexplored concept of how targeting of dual affinity proteins can support organelle attachment, growth and communication.