Fig. 8: A working model depicting PLRG1-mediated alternative splicing driven by USP42 phase separation.

The intrinsically disordered regions mediate the phase separation of USP42 in a positive charge-dependent manner. USP42 DUB activity dominates its efficient incorporation into nuclear speckles to allow enhanced motility. On the contrary, inactivation of the USP domain renders speckle exclusion of USP42, leaving phase-separated USP42 located to speckle periphery with limited motility. However, USP42 is competent to recruit PLRG1 both within and beside nuclear speckles, with nuclear speckle incorporation of PLRG1 conferring efficient splicing activity that is potentially exploited during tumorigenesis to enable stimulated cell growth.