A mechanoresponsive signalling pathway disassembles processing bodies

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A mechanoresponsive signalling pathway disassembles processing bodies Processing bodies (PBs) are cytoplasmic ribonucleoprotein granules that fundamentally regulate gene expression. PBs degrade or sequester mRNA to control what cellular transcripts are translated into protein. PBs are dynamic; they form and disassemble in response to various stimuli. Upon their disassembly, PB-localized mRNAs are relieved of repression, making PBs an important regulatory switch. However, the precise signals that control the `PB switch' are not well defined. With our NSERC-funded research program, we identified a novel mechanoresponsive signalling pathway that elicits PB disassembly, thereby contributing new knowledge to the fundamental understanding of PB control of gene expression. Cells are subject to constant mechanical stimulation that influences behaviour in a process called mechanotransduction. The conversion of external forces into intracellular biochemical signals requires formation thick actin bundles called actin stress fibres (SFs). These activate the mechanoresponsive transcriptional regulator, Yes-associated protein (YAP) to translocate to the nucleus where it regulates gene transcription. We previously showed that the viral KapB protein induced the formation of actin SFs and the disassembly of PBs. Using RNA silencing, we were not able to genetically separate these two phenotypes. Instead, we demonstrated that KapB induction of SFs was required for PB disassembly. Moreover, silencing YAP eliminated KapB-mediated PB disassembly. A biochemically active version of YAP or the exposure of cells to mechanical forces known to activate YAP also caused PB disassembly. These data indicated that YAP was necessary for KapB-mediated PB disassembly, sufficient for PB disassembly and revealed a connection between a mechanoresponsive transcription activator and the regulation of PBs. In a continuation of our NSERC-funded research program, we will further define the signals between mechanical forces, YAP activation and PB disassembly. We propose three specific aims: 1) Characterize mechanical signals that lead to PB disassembly, 2) Identify how mechanical signals elicited from within the cell by KapB influence YAP activation, 3) Elucidate the mechanism of YAP-mediated PB disassembly Impact and Significance: Our studies advance the fundamental understanding of the role of YAP mechanotransduction. We demonstrated that PBs are regulated by mechanical signalling events that alter actin SFs and require the mechanoresponsive transcription factor, YAP. KapB activates, from within the cell, a pathway that links cell shape to post-transcriptional gene regulation via cytoplasmic PBs. This is important because many other stimuli induce actin SFs, actin contractility, changes to cell shape, and active YAP and our work predicts that these stimuli would also cause PB disassembly to modulate cellular gene expression.