COP9 signalosome and PRMT5 methylosome complexes are essential regulators of Lis1-dynein based transport

Cytoplasmic dynein is a minus-end directed microtubule motor essential for retrograde transport in cells. Dynein is tightly regulated by Lis1 where it is reported to stall dynein movement as well as promote formation of active dynein in different model systems. However, the mechanism behind these contrasting functions of Lis1 in regulating dynein is unknown. Here, we identified COP9 Signalosome (CSN) and PRMT5 complexes as critical regulators of Lis1 dependent dynein function. We demonstrated that Lis1 recruits CSN on dynein to facilitate its deneddylation. We show that neddylation of dynein (DIC1 at K42 residue) is essential for assembly of an active dynein complex and subsequent transport of cargoes in cells. Conversely, PRMT5 is recruited to the Lis1-dynein complex where it methylates Lis1. Methylation of Lis1 at R238 position alters its interaction dynamics, leading to dislodging of CSN from dynein resulting in dynein neddylation and activation. In conclusion, we unravel an interplay between CSN, and PRMT5 that provides a sophisticated regulatory mechanism for Lis1’s opposing modes of regulating the dynamics of dynein.