HHV-6 U24 tightly linked to specific E3 ubiquitin ligases

The HHV-6 protein U24, which is expressed early in infection and is thought to be involved in endosomal recycling, appears to play a role in multiple sclerosis (MS). Now, the same group that recently discovered a ligand for U24, hNedd4L-WW3*, has expanded upon their previous experiments to further elucidate the exact interactions and functions of the protein.

The team decided to test how U24 interacts with other Nedd4 family E3 ubiquitin ligases, and they identified the Smurf WW domain as a potential binding partner of U24 based on previous data and their own pull-down assays. Smurf proteins target for degradation a set of proteins that are key players in the TGF-β signaling pathway, which is affected in MS. To determine whether U24 could interfere with this pathway via its negative regulator, the Smurf WW domain, the group tested molecular interactions between the domain and U24.

Three hSmurf2 WW domains were tested, and two of them, hSmurf-WW3 and hSmurf2-WW2+3, were found to moderately bind U24. A phosphorylated version of U24A was found to have the highest affinities, as was also found to be the case with hNedd4L-WW3*. However, the binding affinities of both Smurf domains were significantly weaker than that of hNedd4L-WW3*, suggesting that U24 function is specific to only certain E3 ubiquitin ligases. Because the hSmurf WW/U24 interactions were relatively weak, it is unlikely that U24 plays a significant role in the TGF-β signaling pathway through these proteins.

Find the full paper here, and read more about the team’s findings on hNedd4L-WW3* on our site.