Stress granules: the Tao of RNA triage

Cytoplasmic RNA structures such as stress granules (SGs) and processing bodies (PBs) are functional byproducts of mRNA metabolism, sharing substrate mRNA, dynamic properties and many proteins, but also housing separate components and performing independent functions. Each can exist independently, but when coordinately induced they are often tethered together in a cytosolic dance. Although both self-assemble in response to stress-induced perturbations in translation, several recent reports reveal novel proteins and RNAs that are components of these structures but also perform other cellular functions. Proteins that mediate splicing, transcription, adhesion, signaling and development are all integrated with SG and PB assembly. Thus, these ephemeral bodies represent more than just the dynamic sorting of mRNA between translation and decay. Cytoplasmic RNA structures such as stress granules (SGs) and processing bodies (PBs) are functional byproducts of mRNA metabolism, sharing substrate mRNA, dynamic properties and many proteins, but also housing separate components and performing independent functions. Each can exist independently, but when coordinately induced they are often tethered together in a cytosolic dance. Although both self-assemble in response to stress-induced perturbations in translation, several recent reports reveal novel proteins and RNAs that are components of these structures but also perform other cellular functions. Proteins that mediate splicing, transcription, adhesion, signaling and development are all integrated with SG and PB assembly. Thus, these ephemeral bodies represent more than just the dynamic sorting of mRNA between translation and decay. AU-rich element; an RNA domain, found at the 3′ end of many mRNAs, that promotes silencing or decay. a family of proteins associated with microRNAs, containing both a PIWI domain and a PAZ (Piwi Argonaute Zwille) domain. A subset of Argonaute proteins possess endonuclease ‘slicer’ activity and cleave mRNA, whereas others only silence translation. a regulatory subunit of the eukaryotic translation initiation factor 2 (eIF2) complex, which is part of a larger ternary complex (eIF2–GTP–tRNAiMet) that positions the initiator methionine at the first codon of an mRNA and enables ribosome joining to commence protein translation. Phosphorylation of eIF2α on Ser51 is a requisite signal for the assembly of SGs in cells exposed to environmental stresses. fragile X mental retardation protein; fragile X mental retardation-related protein 1; related proteins that regulate protein translation. The absence of FMRP causes a syndrome of mental retardation due to abnormal brain development. Ras-GTPase-activating protein SH3-domain-binding protein; a multidomain, multifunctional protein that is quantitatively concentrated at SGs in cells subjected to environmental stress. During poliovirus infection, the 3C proteinase cleaves G3BP to prevent SG assembly. a large multidomain protein containing glycine-tryptophan (GW) repeats, associated with miRNAs. GW182 is required for miRNA-induced gene silencing whereas knockdown of GW182 inhibits PB assembly. cytoplasmic foci containing the protein GW182, which are usually identical to processing bodies. It is not yet known whether all metazoan processing bodies contain GW182. small (∼21-nt) RNAs that regulate mRNA expression and stability in metazoan organisms. miRNAs are assembled into RNP structures that contain at least one Argonaute protein and other proteins such as GW182 and FXR1. a protein that binds to poly(A) tails of mRNA and regulates mRNA stability and protein translation. It is a prominent component of SGs but not PBs. mRNAs bound to translating ribosomes. a protein domain rich in hydrophibic amino acids that is capable of assuming two stable conformations, one soluble and one insoluble. The insoluble conformers self-aggregate and are associated with various pathologies. cytoplasmic foci containing components of the 5′ to 3′ mRNA decay machinery, including DCP1a, DCP2, RCK (p54), hedls (GE-1) and edc3 (enhancer of decapping 3). ribonucleoprotein; an RNA–protein complex, often containing multiple proteins bound to the same RNA. mRNPs contain mRNA bound to proteins but not to ribosomes. a rapid change in environmental conditions. In this review, we refer to stresses such as heat shock, exposure to oxidants, unfolded proteins or double-stranded RNA, that activate an eIF2α kinase. transient, dynamic cytoplasmic sites containing aggregates of mRNA bound to 48S preinitiation factors. T cell internal antigen-1, TIA-1-related; two related mRNA-binding proteins that contain three RNA-recognition motifs and a C-terminal prion-related domain, which recognize specific mRNAs and promote their silencing and decay. tristetraprolin; a zinc-finger-containing protein that promotes the decay of ARE-containing mRNAs at PBs.