Abstract
RNA granules are large messenger ribonucleoprotein complexes that regulate translation and mRNA translocation to control the timing and location of protein synthesis. The regulation of RNA granule assembly and disassembly is a structural basis of translational control, and its disorder is implicated in degenerative disease. Here, we used proteomic analysis to identify proteins associated with RNA granule protein 105 (RNG105)/caprin1, an RNA-binding protein in RNA granules. Among the identified proteins, we focused on nuclear factor (NF) 45 and its binding partner, nuclear factor associated with dsRNA 2 (NFAR2), and we demonstrated that NF45 promotes disassembly of RNA granules, whereas NFAR2 enhances the assembly of RNA granules in cultured cells. The GQSY domain of NFAR2 was required to associate with messenger ribonucleoprotein complexes containing RNG105/caprin1, and it was structurally and functionally related to the low complexity sequence domain of the fused in sarcoma protein, which drives the assembly of RNA granules. Another domain of NFAR2, the DZF domain, was dispensable for association with the RNG105 complex, but it was involved in positive and negative regulation of RNA granule assembly by being phosphorylated at double-stranded RNA-activated kinase sites and by association with NF45, respectively. These results suggest a novel molecular mechanism for the modulation of RNA granule assembly and disassembly by NFAR2, NF45, and phosphorylation at double-stranded RNA-activated kinase PKR sites.
Highlights
RNA granules are associated with translational control and neurodegenerative disease
We focused on nuclear factor (NF) 45 and its binding partner, nuclear factor associated with doublestranded RNA (dsRNA) 2 (NFAR2), and we demonstrated that nuclear factor 45 (NF45) promotes disassembly of RNA granules, whereas Nuclear factor associated with dsRNA 2 (NFAR2) enhances the assembly of RNA granules in cultured cells
It has been unclear whether the two NFAR splice variants, Nuclear factor associated with dsRNA 1 (NFAR1) and NFAR2, have different properties from one another, we demonstrated that NFAR2, but not NFAR1, has the ability to localize to and enhance the assembly of RNA granules
Summary
RNA granules are associated with translational control and neurodegenerative disease. The GQSY domain of NFAR2 was required to associate with messenger ribonucleoprotein complexes containing RNG105/caprin, and it was structurally and functionally related to the low complexity sequence domain of the fused in sarcoma protein, which drives the assembly of RNA granules Another domain of NFAR2, the DZF domain, was dispensable for association with the RNG105 complex, but it was involved in positive and negative regulation of RNA granule assembly by being phosphorylated at double-stranded RNAactivated kinase sites and by association with NF45, respectively. Recent studies proposed that degenerative disease-associated mutations in RNA granule components, e.g. TAR DNA-binding protein 43 (TDP-43), fused in sarcoma/translocated in sarcoma (FUS2/TLS), heterogeneous nuclear ribonucleoprotein (hnRNP) A2B1 and hnRNPA1 enhance their incorporation into RNA granules and promote RNA granule aggregation (6 – 8) These proteins contain prionlike low complexity (LC) sequence domains, which are responsible for RNA granule assembly under normal conditions and the formation of pathological aggregates in their mutant forms (6 –9). These results suggest a novel mechanism of RNA granule assembly and disassembly regulated by NFAR2 phosphorylation by PKR and NF45
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