Translational Control of Cytochrome c by RNA-Binding Proteins TIA-1 and HuR

Abstract

Stresses affecting the endoplasmic reticulum (ER) globally modulate gene expression patterns by altering posttranscriptional processes such as translation. Here, we use tunicamycin (Tn) to investigate ER stress-triggered changes in the translation of cytochrome c, a pivotal regulator of apoptosis. We identified two RNA-binding proteins that associate with its ∼900-bp-long, adenine- and uridine-rich 3′ untranslated region (UTR): HuR, which displayed affinity for several regions of the cytochrome c 3′UTR, and T-cell-restricted intracellular antigen 1 (TIA-1), which preferentially bound the segment proximal to the coding region. HuR did not appear to influence the cytochrome c mRNA levels but instead promoted cytochrome c translation, as HuR silencing greatly diminished the levels of nascent cytochrome c protein. By contrast, TIA-1 functioned as a translational repressor of cytochrome c, with interventions to silence TIA-1 dramatically increasing cytochrome c translation. Following treatment with Tn, HuR binding to cytochrome c mRNA decreased, and both the presence of cytochrome c mRNA within actively translating polysomes and the rate of cytochrome c translation declined. Taken together, our data suggest that the translation rate of cytochrome c is determined by the opposing influences of HuR and TIA-1 upon the cytochrome c mRNA. Under unstressed conditions, cytochrome c mRNA is actively translated, but in response to ER stress agents, both HuR and TIA-1 contribute to lowering its biosynthesis rate. We propose that HuR and TIA-1 function coordinately to maintain precise levels of cytochrome c production under unstimulated conditions and to modify cytochrome c translation when damaged cells are faced with molecular decisions to follow a prosurvival or a prodeath path.

miR-519 reduces cell proliferation by lowering RNA-binding protein HuR levels

“…One interesting facet of this study is that it describes an example of one type of posttranscriptional regulator (a miRNA) controlling the expression of another type of posttranscriptional regulator (an RBP). Previous reports showed that some TTR-RBPs can modulate posttranscriptionally the expression of other TTR-RBPs (3,31); the present study provides a prominent example of a miRNA regulating a TTR-RBP. The fact that HuR enhances the stability of many target mRNAs raises an intriguing possibility for further consideration: if miR-519 is found to trigger the decay of a putative target mRNA, it is possible that the effect is indirect, should HuR be a stabilizing TTR-RBP for that particular mRNA.…”

Inhibition of miR-9 de-represses HuR and DICER1 and impairs Hodgkin lymphoma tumour outgrowth in vivo

“…15,32 HuR is a ubiquitous member of the Hu family of proteins 33 that can regulate mRNA stability and translation by binding to ARE-motifs and interacting with other ARE-binding proteins, such as TTP, AUF1 and KH-type splicing regulatory protein. 34,35 Despite the fact that HuR is often reported as a stabilizing factor for ARE-containing mRNAs, its ability to synergize with TIA-1 and to inhibit translation of cytokines is also well known. 36 In the present study, we show that miR-9 directly targets HuR and Dicer1 for posttranscriptional repression.…”

Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged

“…Among the earliest functions attributed to TIA-1 and TIAR was the ability to bind mRNAs and recruit them to cytoplasmic bodies (known as stress granules) in response to cellular stress such as heat shock (Kedersha et al 1999). Both proteins have also been found to bind AU-rich elements (AREs) and act as translational repressors (Piecyk et al 2000;Kawai et al 2006;Kim et al 2007). TIA-1 and TIAR have been shown to be regulators of the inflammatory response that function by silencing translation of key mediators of inflammation, such as TNF-a and COX-2 (Piecyk et al 2000;Lopez de Silanes et al 2005a).…”