In vertebrates, the majority of mRNAs that encode secreted, membrane-bound or 
mitochondrial proteins contain RNA elements that activate an alternative mRNA 
nuclear export (ALREX) pathway. Here we demonstrate that mRNAs containing 
ALREX-promoting elements are trafficked through nuclear speckles. Although 
ALREX-promoting elements enhance nuclear speckle localization, additional 
features within the mRNA largely drive this process. Depletion of two 
TREX-associated RNA helicases, UAP56 and its paralog URH49, or inhibition of the 
TREX-associated nuclear transport factor, TAP, not only inhibits ALREX, but also 
appears to trap these mRNAs in nuclear speckles. mRNAs that contain 
ALREX-promoting elements associate with UAP56 in vivo. Finally, we demonstrate 
that mRNAs lacking a poly(A)-tail are not efficiently exported by the ALREX 
pathway and show enhanced association with nuclear speckles. Our data suggest 
that within the speckle, ALREX-promoting elements, in conjunction with the 
poly(A)-tail, likely stimulate UAP56/URH49 and TAP dependent steps that lead to 
the eventual egress of the export-competent mRNP from these structures.