SUMMARY Amyloid bodies (A-bodies) are inducible membraneless nuclear compartments composed of heterogeneous proteins that adopt an amyloid-like state. A-bodies are seeded by noncoding RNA derived from stimuli-specific loci of the rDNA intergenic spacer (rIGSRNA). This raises the question of how rIGSRNA recruits a large population of diverse proteins to confer A-body identity. Here, we show that long low-complexity dinucleotide repeats operate as the architectural determinants of rIGSRNA. On stimulus, clusters of rIGSRNA with simple cytosine/ uracil (CU) or adenosine/guanine (AG) repeats spanning hundreds of nucleotides accumulate in the nucleolar area. The low-complexity sequences facilitate charge-based interactions with short cationic peptides to produce multiple nucleolar liquid-like foci. Local concentration of proteins with fibrillation propensity in these nucleolar foci induces the formation of an amyloidogenic liquid phase that seeds Abodies. These results demonstrate the physiological importance of low-complexity RNA and repetitive regions of genomethe genome often dismissed as “junk” DNA.
b Tristetraprolin (TTP) regulates the expression of AU-rich element-containing mRNAs through promoting the degradation and repressing the translation of target mRNA. While the mechanism for promoting target mRNA degradation has been extensively studied, the mechanism underlying translational repression is not well established. Here, we show that TTP recruits eukaryotic initiation factor 4E2 (eIF4E2) to repress target mRNA translation. TTP interacted with eIF4E2 but not with eIF4E. Overexpression of eIF4E2 enhanced TTP-mediated translational repression, and downregulation of endogenous eIF4E2 or overexpression of a truncation mutant of eIF4E2 impaired TTP-mediated translational repression. Overexpression of an eIF4E2 mutant that lost the cap-binding activity also impaired TTP's activity, suggesting that the cap-binding activity of eIF4E2 is important in TTPmediated translational repression. We further show that TTP promoted eIF4E2 binding to target mRNA. These results imply that TTP recruits eIF4E2 to compete with eIF4E to repress the translation of target mRNA. This notion is supported by the finding that downregulation of endogenous eIF4E2 increased the production of tumor necrosis factor alpha (TNF-␣) protein without affecting the mRNA levels in THP-1 cells. Collectively, these results uncover a novel mechanism by which TTP represses target mRNA translation.T ristetraprolin (TTP) plays important roles in immunity, development, and tumorigenesis by posttranscriptionally regulating the expression of a variety of genes (1). For example, TTP regulates the expression of tumor necrosis factor alpha (TNF-␣) (2). Knockout of TTP in mice results in TNF-␣ excess and causes severe immune disorders (2, 3).TTP specifically recognizes AU-rich elements (AREs), which are cis elements with tandem AUUUA-like motifs in a context rich in A and/or U, mainly located in the 3= untranslated region (3= UTR) of the mRNAs of stringently regulated genes, such as cytokine and growth factor genes and proto-oncogenes (4, 5). TTP directly binds to ARE motifs and recruits cellular mRNA decay enzymes, including the deadenylase complex CCR4-NOT, decapping complex DCP1a/DCP2, 3=-5= exoribonuclease complex exosome, and 5=-3= exoribonuclease Xrn1, to degrade target mRNAs (6)(7)(8)(9)(10)(11)(12)(13)(14). This activity of TTP is regulated by phosphorylation modification (6-14). There is increasing evidence suggesting that TTP also regulates the translation of target mRNAs. It has been reported elsewhere that TTP associates with polysomes (15, 16) and that a TTP-interacting protein, cullin 4B, promotes the loading of TTP-associated TNF-␣ mRNA complex onto polysomes (17). Recently, Qi et al. reported that TTP inhibits the translation of TNF-␣ in an ARE-dependent manner and the RNA helicase RCK is involved in this process (18). In addition, Tiedje et al. reported that TTP represses the translation of TNF-␣ through competing with HuR to bind to ARE (19). Nonetheless, detailed mechanisms underlying TTP-mediated translational repression are not well esta...
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