Biphasic SMN condensates safeguard stress-induced cytoplasmic mislocalization of splicing RNPs

Abstract Biogenesis of UsnRNPs occurs in distinct steps in the nucleus and the cytoplasm. Sequential cytoplasmic actions of CLNS1A in the PRMT5 complex and of the SMN complex assemble the Sm core structure consisting of RNA and proteins. Nuclear SMN, condensed in Cajal Bodies, promotes late maturation steps. Whether cytoplasmic SMN undergoes condensation, and how this contributes to UsnRNP biogenesis or homeostasis, is poorly defined. Here, we show that molecular crowding stress induces rapid, reversible condensation of cytoplasmic SMN into droplets and filamentous assemblies, S-bodies, that sequester mislocalized cytoplasmic UsnRNPs along microtubules. During stress recovery, S-bodies undergo microtubule-dependent reorganization into split SMN–CLNS1A condensates, Janus bodies, that promote clearance of mislocalized UsnRNPs. Strikingly, cellular models of the SMN-associated disease spinal muscular atrophy fail to assemble S-bodies and to clear cytoplasmic UsnRNPs. Our findings identify stress-induced SMN condensation as a mechanism to buffer and resolve cytoplasmic UsnRNP mislocalization and reveal impaired tolerance to molecular crowding as a hallmark of spinal muscular atrophy.