The goals of this grant are to understand the assembly, dynamics, and functions of stress granules in the control of gene expression. Stress granules are cytoplasmic granules of untranslating mRNAs and proteins that form when translation initiation is limiting. Stress granules are important for three reasons. First, they sequester mRNAs and mRNA binding proteins and are thought to play a role in regulating the translation or degradation of its resident mRNAs, particularly during stress. Second, assemblies related to stress granules form in neurons and play a role in modulating synaptic plasticity (McCann et al., 2011; Barbee et al., 2006). Thus, understanding stress granules will help to understand other similar mRNP assemblies. Finally, aberrant stress granule accumulation appears to be a causative event in a multisystem pathology, referred to as inclusion body myopathy (IBM) that includes Amyotrophic Lateral Sclerosis (ALS), Frontotemporal lobar degeneration (FTLD), Paget's disease of bone and some muscle myopathies. These diseases can be caused by mutations in RNA binding proteins, such as hnRNPA1 or TDP-43, which increase stress granule assembly and amyloid formation, or by mutations in the AAA-ATPase VCP, which decrease stress granule clearance. Moreover, these diseases are characterized by the presence of cytoplasmic RNA-protein aggregates that contain markers of stress granules. Given this importance in both normal stress responses and in pathological conditions, an understanding of normal and aberrant stress granule formation and function is critical. In this grant, we build on our recent analyses of the stress granule proteome and transcriptome to determine the effect of stress granule formation on mRNA function, the mechanisms that target mRNAs to stress granules, and the novel role of mRNA-mRNA interactions in trans on the assembly and maintenance of stress granules. The specific questions addressed in this proposal are: I) What is the impact of stress granule assembly on mRNA stability and decay? II) What are the mechanisms of mRNA partitioning into stress granules? III) What is the role of RNA-RNA interactions in stress granule assembly? Completion of these aims will reveal fundamental principles of stress granule assembly and function, including insights into how pathological RNP granules form and impact gene expression in affected tissues.
This project focuses on understanding the mechanisms by which mRNAs accumulate in stress granules, and how stress granule formation affects mRNA translation and stability. The work also addresses the mechanisms by which mRNAs accumulate in pathological RNP granules and how this accumulation might affect disease progression. A mechanistic understanding of how mRNAs accumulate in both normal and pathological stress granules may suggest possible therapies for some neurodegenerative diseases.
| Vogler, Thomas O; Wheeler, Joshua R; Nguyen, Eric D et al. (2018) TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle. Nature 563:508-513 |
| Van Treeck, Briana; Parker, Roy (2018) Emerging Roles for Intermolecular RNA-RNA Interactions in RNP Assemblies. Cell 174:791-802 |
| Protter, David S W; Rao, Bhalchandra S; Van Treeck, Briana et al. (2018) Intrinsically Disordered Regions Can Contribute Promiscuous Interactions to RNP Granule Assembly. Cell Rep 22:1401-1412 |
| Lester, Evan; Parker, Roy (2018) The Tau of Nuclear-Cytoplasmic Transport. Neuron 99:869-871 |
| Braselmann, Esther; Wierzba, Aleksandra J; Polaski, Jacob T et al. (2018) A multicolor riboswitch-based platform for imaging of RNA in live mammalian cells. Nat Chem Biol 14:964-971 |
| Khong, Anthony; Jain, Saumya; Matheny, Tyler et al. (2018) Isolation of mammalian stress granule cores for RNA-Seq analysis. Methods 137:49-54 |
| Van Treeck, Briana; Protter, David S W; Matheny, Tyler et al. (2018) RNA self-assembly contributes to stress granule formation and defining the stress granule transcriptome. Proc Natl Acad Sci U S A 115:2734-2739 |
| Wheeler, Joshua R; Jain, Saumya; Khong, Anthony et al. (2017) Isolation of yeast and mammalian stress granule cores. Methods 126:12-17 |
| Walters, Robert W; Matheny, Tyler; Mizoue, Laura S et al. (2017) Identification of NAD+ capped mRNAs in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 114:480-485 |
| Khong, Anthony; Matheny, Tyler; Jain, Saumya et al. (2017) The Stress Granule Transcriptome Reveals Principles of mRNA Accumulation in Stress Granules. Mol Cell 68:808-820.e5 |
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