Aksenova, V.; Giordano, E.; Esnault-Petrov, C.; Arnaoutov, A.; Dasso, M.

The TRanscription and EXport 2 (TREX2) complex plays a central role in bridging the transcription and export machinery. Although the subunits of TREX2 work together, they exhibit differences in expression, localization, and dynamics, suggesting distinct cellular roles. To understand the roles of individual TREX2 components, we have characterized their interactomes and identified novel, evolutionarily conserved SAC3(PCI-fold)-based subcomplexes for one of its subunits, PCID2, which acts as a scaffold for mutually exclusive yet structurally related subcomplexes. GANP, LENG8, and SAC3D1 each possess a SAC3-homology domain and exhibit extensive conservation with the ySAC3 domain. The subunits GANP, LENG8, and SAC3D1 have alternative intracellular localization and direct PCID2 to the nuclear envelope, nuclear speckles and cytosol, respectively. LENG8 localization in nuclear speckles and its network of binding partners indicate extensive interactions with the mRNA processing machinery. 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.