Extracellular vesicles (EVs)are involved in the progression of diverse diseases. Therefore, targeting EVbiogenesis is a potential strategy for the treatment of the related diseases,which urges an improved understanding of EV biogenesis. During the biogenesisof EV subset, exosomes, invagination of the plasma membranes forms early endosomeswhich mature into late endosomes and multivesicular bodies (MVBs) eventually. MVBsfuse with not only the plasma membranes to release EVs but also lysosomes fordegradation. Rab7 participates in the lysosomal targeting of MVBs. However, theproteins on MVB that directly bind Rab7, causing MVB recruitment of Rab7 remainunidentified.
The research team led byProf. Cai Zhijian from the Zhejiang University School of Medicine discoveredthe novel mechanism of EV biogenesis. The findings were published in an articletitled “Neddylation of Coro1a determines the fate of multivesicular bodiesand biogenesis of extracellular vesicles” in the journal Journal ofExtracellular Vesicles on October 8.
“Ubiquitin andubiquitin-like modifications contribute to the regulation EV biogenesis,” saidCai, “Neddylation refers to the covalent attachment of the ubiquitin-likeprotein NEDD8 to a target protein, which is related to neurodegenerativediseases, cancer and infection. Whether neddylation modification can alsoregulate EV biogenesis has yet to be explored.”
In this study, researchers foundthat Coro1a would undergo neddylation modification at K233 by TRIM4. NeddylatedCoro1a is associated with the MVB membrane and facilitates MVB recruitment andactivation of Rab7 by directly binding Rab7. Subsequently, MVBs are targeted tolysosomes for degradation in a Rab7-dependent manner, leading to reduced EVsecretion.
NEDD8-Coro1a mediates therecruitment of Rab7 to MVBs
Furthermore, we foundMC38-Coro1a-K233R tumour-bearing mice exhibited faster tumour growth andshorter survival than MC38-Coro1a tumourbearing mice, inhibiting that adecrease in neddylated Coro1a enhances the production of tumour EVs, thereby promotingtumour progression, indicating that neddylated Coro1a is an ideal target forthe regulation of EV biogenesis.
Inhibition of Coro1aneddylation promotes tumour progression by increasing EV secretion
“Our research identified anovel substrate of neddylation and revealed an unknown mechanism for MVBrecruitment of Rab7, thus providing new insight into the regulation of EVbiogenesis,” said Prof. Cai.
