UBAP2L Forms Distinct Cores that Act in Nucleating Stress Granules Upstream of G3BP1

Stress granules (SGs) are membraneless organelles that form in eukaryotic cells after stress exposure [1] (reviewed in [2–4]). Following translation inhibition, polysome disassembly releases 48S preinitiation complexes (PICs). mRNA, PICs, and other proteins coalesce in SG cores [1, 5–7]. SG cores recruit a dynamic shell, whose properties are dominated by weak interactions between proteins and RNAs [8–10]. The structure and assembly of SGs and how different components contribute to their formation are not fully understood. Using super-resolution and expansion microscopy, we find that the SG component UBAP2L [11, 12] and the core protein G3BP1 [5, 11–13] occupy different domains inside SGs. UBAP2L displays typical properties of a core protein, indicating that cores of different compositions coexist inside the same granule. Consistent with a role as a core protein, UBAP2L is required for SG assembly in several stress conditions. Our reverse genetic and cell biology experiments suggest that UBAP2L forms granules independent of G3BP1 and 2 but does not interfere with stress-induced translational inhibition. We propose a model in which UBAP2L is an essential SG nucleator that acts upstream of G3BP1 and 2 and facilitates G3BP1 core formation and SG assembly and growth. [Display omitted] •UBAP2L displays properties of a core component of stress granules•UBAP2L and G3BP1 form stress granule cores that do not always colocalize•UBAP2L forms small RNP granules independent of G3BP1•UBAP2L functions upstream of G3BP1 in stress granule assembly Stress granules (SGs) are formed by a stable core and a dynamic shell. Cirillo, Cieren, et al. demonstrate that UBAP2L is an SG core component that does not always colocalize with the previously identified core protein G3BP1. UBAP2L is required for SG formation in several stress conditions and forms SGs independent and upstream of G3BP proteins.