mRNP granules. Assembly, function, and connections with disease

Abstract

Messenger ribonucleoprotein (mRNP) granules are dynamic, self-assembling structures that harbor non-translating mRNAs bound by various proteins that regulate mRNA translation, localization, and turnover. Their importance in gene expression regulation is far reaching, ranging from precise spatial-temporal control of mRNAs that drive developmental programs in oocytes and embryos, to similarly exquisite control of mRNAs in neurons that underpin synaptic plasticity, and thus, memory formation. Analysis of mRNP granules in their various contexts has revealed common themes of assembly, disassembly, and modes of mRNA regulation, yet new studies continue to reveal unexpected and important findings, such as links between aberrant mRNP granule assembly and neurodegenerative disease. Continued study of these enigmatic structures thus promises fascinating new insights into cellular function, and may also suggest novel therapeutic strategies in various disease states.

Keywords: 4E-BP, eIF4E binding protein; ALS, amyotropic lateral sclerosis; FRAP, fluorescence recovery after photobleaching; FTLD, frontotemporal lobar degeneration; HSP, heat shock protein; IMC, inter-mitochondrial cement; MSP, multi-system proteinopathy; P-bodies; RISC, RNA induced silencing complex; decay; germ granules; mRNA; mRNP, messenger ribonucleoprotein; neurodegenerative disease; neuronal transport granules; repression; stress granules; translation.

Figure 1.

mRNP granules across biology. (A) Graphic of Drosophila egg chamber indicates interaction of multiple mRNP granule types in the cytoplasm of nurse cells, and modes of transport to the germ plasm. (B) Gonad of a C.elegans hermaphrodite indicates “assembly line” maturation, from mitotic stem cells at distal end (top right) to oocytes at proximal end (bottom right). P-granules remain docked with nucleus until diplotene, then re-localize to the cytoplasm with nuclear pore components. P-bodies are distributed throughout the shared cytoplasm. (Panels A and B adapted from Voronina et al., 2011 and reproduced with permission). (C) Simplified neuronal cell schematic demonstrating specific localization of transport granules in dendrites and the axon. Interactions with P-bodies and transport along microtubules are highlighted. (D) Stressed somatic cell, indicating typical distribution of stress granules (often peri-nuclear) and P-bodies, which often dock with stress granules. Interactions of both granules with microtubules also highlighted.

Figure 2.

Modes of mRNP granule assembly and disassembly. Circled numbers refer to text in figures describing putative assembly/disassembly mechanisms of mRNP granules. Note, the use and relative importance of these likely vary depending on granule type and context. Abbreviations: RBP, RNA binding protein; Td, tudor domain protein; Me, methylation; Ub, ubiquitination; P, phosphorylation; HSP, heat shock protein; ATG, autophagy factor.