HuR and myogenesis: Being in the right place at the right time

Abstract

The process of muscle cell differentiation into myotubes, termed myogenesis, depends on a complex coordination of myogenic factors, many of which are regulated post-transcriptionally. HuR, an mRNA-binding protein, is responsible for regulating the expression of several such myogenic factors by stabilizing their mRNAs. The critical role for HuR in myogenesis also involves the nucleocytoplasmic shuttling ability of this protein. Indeed, in order to perform its stabilizing functions, HuR must accumulate in the cytoplasm. This requires its dissociation from the import factor Transportin 2 (TRN2) which is actually caused by the cleavage of a portion of cytoplasmic HuR. In this review, we describe the roles of HuR during myogenesis, and the mechanisms regulating its cytoplasmic accumulation. This article is part of a Special Issue entitled: Regulation of Signaling and Cellular Fate through Modulation of Nuclear Protein Import.

Post-transcriptional regulation of Pabpn1 by the RNA binding protein HuR

“…To determine whether a change in the steady-state localization of HuR correlates with differential regulation of Pabpn1 expression in myoblasts and myotubes, we assessed the subcellular localization of HuR in these cells using biochemical fractionation (Figure 8C). As expected (30,70), HuR is primarily nuclear in both C2C12 myoblasts and C2C12 myotubes (Figure 8C). However, there is an increase in the level of cytoplasmic HuR in C2C12 myotubes compared to C2C12 myoblasts (Figure 8C), consistent with previous observations (67,71,72).…”

“…Although the steady-state localization of HuR is predominantly nuclear, HuR shuttles between the nucleus and the cytoplasm (69). Phosphorylation can regulate HuR localization (70), which can affect HuR-mediated regulation of RNA target stability as most properly processed mRNAs are degraded in the cytoplasm (77). Our data show that HuR is primarily nuclear in both C2C12 myoblasts and C2C12 myotubes (30).…”

Destabilization of nucleophosmin mRNA by the HuR/KSRP complex is required for muscle fibre formation

“…Myogenesis requires the activation of muscle-specific promyogenic factors that are expressed at specific steps of the myogenic process and act in a sequential manner. We and others have demonstrated that the expression of genes encoding some of these promyogenic factors such as MyoD, myogenin and the cyclin-dependent kinase p21, are not only regulated at the transcriptional level but are also modulated posttranscriptionally 3–8 . Indeed, modulating the half-lives of these mRNAs plays an important role in their expression.…”

“…HuR, a member of the ELAV family of RNA binding proteins, specifically binds to AREs located in the 3′UTRs of its target transcripts 8–12 leading to their stability that, which in turn enhances the expression of the encoded proteins 5,7 . In addition to mRNA stability, HuR modulates the nucleocytoplasmic movement and the translation of target transcripts 13–16 .…”

“…In the cytoplasm, HuR is cleaved by caspase-3 at its 226 th residue, an Asp (D), generating two cleavage products (HuR-CPs: -CP1, 24kDa and -CP2, 8kDa). These HuR-CPs, generated from ~50% of cytoplasmic HuR, are required for muscle fiber formation 4,8 . Indeed, while wtHuR can rescue myogenesis in cells depleted of endogenous HuR, the non-cleavable HuRD226A mutant failed to do so 4,8 .…”