Wnt protein hitches a ride on exosomes

Researchers from the Ottawa HospitalResearch Institute and the University of Ottawa in Canada, along with researchers from the Centre for Genomic Regulation at the Barcelona Institute for Science and Technology and the Center for Cooperative Research in Biosciences in Spain, have found the mechanism for how a member of the Wnt protein family manages to hitch a ride on cellular exosomes. The new work was published in Science Advances (2024, DOI: 10.1126/sciadv.ado5914).

Wnt proteins are important signalers for a wide range of processes, including regeneration after an injury and proliferation of stem cells. But because they are hydrophobic and insoluble, they don’t travel very far on their own. Despite this, long-range, paracrine Wnt signaling has been observed, and one explanation is that they stick to the outside of cell packages called exosomes. These exosomes are pouches that pinch off from the cell membrane and contain proteins and RNA. Despite observing this signaling, scientists weren’t sure how the Wnt proteins were able to stick to the exosomes before traveling long distances.

One of these Wnt proteins, Wnt7a, is upregulated after skeletal muscle injury, and intramuscular injections of Wnt7a into mouse models of Duchenne muscular dystrophy can slow the progression of the disease. Wnt7a’s insolubility makes it problematic as a possible therapeutic agent, but if it can attach to exosomes, it may be able to get where it needs to go.

The researchers found that Wnt7a is indeed able toattach to exosomes—and that it has a designated amino acid sequence for this very purpose. Wnt7a contains a signal sequence of 18 amino acids that binds to two coatomers, COPA and COPB2, that are present on the exosomes of muscle cells. Attached to the exosome, Wnt7a is transported to the exosome’s destination. When the researchers transferred this sequence to an unrelated peptide from a bacterial enzyme, they found that the peptide was able to stick to the exosomes as well.

Julia Gross, a professor of biochemistry at the Health and Medical University Potsdam who was not involved with the research, says the paper is thorough in showing that this domain exists, but the larger journey of Wnt7a is missing. While the biochemical evidence supports that this domain allows Wnt7a to stick to the exosome, it’s unclear how Wnt7a is trafficked to the outside of the exosome after it is translated, and if this peptide is necessary to travel to the exosome, not just stick to it.

Michael Rudnicki, one of the paper’s lead authors, says that this advance could accelerate developing Wnt7a and exosomes as a possible therapeutic, though much more work needs to be done.

“One can target, potentially, any protein to the surface of exosomes, and this is important for a therapeutic application and for targeting those exosomes to particular cell types or tissues,” he says..