Research summary

Exosomes are vesicles released from various cell types via the Multivesicular Body (MVB), which encapsulates specific proteins and are reincorporated into target cells. In diseases states such as cancer metastasis and neurodegeneration, the propagation of malignant proteins through exosomes is responsible for the expansion of the foci. It has been reported that some molecules are sorted to exosomes by ubiquitination (Putz et al., Sci Signal 2012; Smith et al., J Immunol 2015). However, the mechanism of sorting of specific proteins to exosomes is not fully understood. It is also known that inhibiting autophagy increases exosome release, and vice versa (Abdulrahman et al., JBC 2018; Minakaki et al., Autophagy 2018; Miranda et al., Nat Commun 2018). However, the regulatory mechanism is still unknown.
The applicant identified a novel post-translational modification by UBL3 and found that the UBL3 modification regulates protein sorting to exosomes (Ageta et al., Nature Commun 2018). We compared the sorting of GFP-tagged ubiquitin, SUMO, and UBL3 to exosomes and confirmed that ubiquitinated proteins are also sorted to exosomes. These results indicate that the sorting of specific proteins is not entirely regulated by UBL3, but is partially regulated by ubiquitination. In this study, by using the UBL3 chemotechnologies, we will examine the relationship between "ubiquitination modification and autophagy regulation" and "UBL3 modification", and search for effective drugs for exosome-related diseases.