Physiological networks and disease functions of RNA‐binding protein AUF1

Abstract

Regulated messenger RNA (mRNA) decay is an essential mechanism that governs proper control of gene expression. In fact, many of the most physiologically potent proteins are encoded by short-lived mRNAs, many of which contain AU-rich elements (AREs) in their 3'-untranslated region (3'-UTR). AREs target mRNAs for post-transcriptional regulation, generally rapid decay, but also stabilization and translation inhibition. AREs control mRNA turnover and translation activities through association with trans-acting RNA-binding proteins that display high affinity for these AU-rich regulatory elements. AU-rich element RNA-binding protein (AUF1), also known as heterogeneous nuclear ribonucleoprotein D (HNRNPD), is an extensively studied AU-rich binding protein (AUBP). AUF1 has been shown to regulate ARE-mRNA turnover, primarily functioning to promote rapid ARE-mRNA degradation. In certain cellular contexts, AUF1 has also been shown to regulate gene expression at the translational and even the transcriptional level. AUF1 comprises a family of four related protein isoforms derived from a common pre-mRNA by differential exon splicing. AUF1 isoforms have been shown to display multiple and distinct functions that include the ability to target ARE-mRNA stability or decay, and transcriptional activation of certain genes that is controlled by their differential subcellular locations, expression levels, and post-translational modifications. AUF1 has been implicated in controlling a variety of physiological functions through its ability to regulate the expression of numerous mRNAs containing 3'-UTR AREs, thereby coordinating functionally related pathways. This review highlights the physiological functions of AUF1-mediated regulation of mRNA and gene expression, and the consequences of deficient AUF1 levels in different physiological settings.

Targeted mRNA Decay by RNA Binding Protein AUF1 Regulates Adult Muscle Stem Cell Fate, Promoting Skeletal Muscle Integrity

“…Many key regulatory mRNAs are controlled through post-transcriptional mechanisms, typically the targeted destabilization of the mRNA, its selective translation, or both (Moore et al, 2014). The regulated stability of mRNAs generally comprises those that must respond quickly in abundance to changing stimuli.…”

“…Many physiologically potent proteins are encoded by short-lived mRNAs with half-lives of minutes, in which mRNA destabilization is conferred by AREs in the 3′ untranslated region (3′UTR). A common ARE motif consists of the sequence AUUUA, typically repeated multiple times in the 3′UTR, often contiguously (Moore et al, 2014). The ARE is purely a cis-acing element that serves as a binding site for regulatory proteins known as AU-rich binding proteins (AUBPs) which bind the ARE with high affinity and control mRNA stability or translation.…”

“…AU-rich binding factor 1 (AUF1, HNRNPD) binds certain ARE-mRNAs to promote their rapid degradation through association with trans-acting RNA binding proteins (Moore et al, 2014). AUF1 primarily functions as an ARE-mRNA decay factor (Moore et al, 2014); von Roretz et al, 2011).…”

“…AUF1 primarily functions as an ARE-mRNA decay factor (Moore et al, 2014); von Roretz et al, 2011). AUF1 consists of four related protein isoforms named for their molecular weights (p37, p40, p42, p45), derived by differential exon splicing of a common pre-mRNA (Wagner et al, 1998).…”

Expression of ARE-binding proteins AUF1 and HuR in follicular adenoma and carcinoma of thyroid gland

“…Both proteins were reported to exert opposite effects on target transcripts. HuR is known to enhance their stability and/or translation, while AUF1 which is expressed as four isoforms causes generally the decay of some mRNAs [10,11,12,13,14,15].…”