TREX2 component PCID2 scaffolds alternative SAC3-based subcomplexes with distinct RNA processing and export function

The TREX2 complex bridges transcription and RNA export. Its subunits show differences in expression, localization, and dynamics, suggesting distinct cellular roles. To understand the roles of individual TREX2 components, we characterized their interactomes. We identified novel, evolutionarily conserved SAC3(PCI-fold)-based subcomplexes with its PCID2 subunit. PCID2 acts as a scaffold for mutually exclusive yet structurally related subcomplexes with GANP, LENG8, and SAC3D1. These subcomplexes have alternative localization at the nuclear envelope, nuclear speckles and cytosol. LENG8 localizes in nuclear speckles and interacts extensively with the mRNA processing factors. LENG8 depletion alters mRNA processing and polyadenylation site usage. LENG8 thus acts upstream of the canonical TREX2 complex, in which PCID2 cooperates with GANP in mRNA export. Together, our findings reveal that TREX2 is not a uniform complex but a modular system, in which TREX2 subunits can assemble into functionally distinct subcomplexes through interacting partners that define their specificity and alternative functions. HIGHLIGHTSO_LITREX2 subunits play distinct roles in RNA retention and exhibit subunit-specific preference for interactions with different protein partners C_LIO_LIPCID2 forms mutually exclusive subcomplexes with GANP, LENG8, and SAC3D1 C_LIO_LIGANP, LENG8, and SAC3D1 alter PCID2 intracellular localization C_LIO_LILENG8 is a nuclear speckle protein that modulates alternative mRNA processing C_LI