RNA–Binding Protein HuD as a Versatile Factor in Neuronal and Non–Neuronal Systems

SIMPLE SUMMARY: Tight regulation of gene expression is critical for various biological processes such as proliferation, development, differentiation, and death; its dysregulation is linked to the pathogenesis of diseases. Gene expression is dynamically regulated by numerous factors at DNA, RNA, and protein levels, and RNA binding proteins (RBPs) and non–coding RNAs play important roles in the regulation of RNA metabolisms. RBPs govern a diverse spectrum of RNA metabolism by recognizing and binding to the secondary structure or the certain sequence of target mRNAs, and their malfunctions caused by aberrant expression or mutation are implicated in disease pathology. HuD, an RBP in the human antigen (Hu) family, has been studied as a pivotal regulator of gene expression in neuronal systems; however, accumulating evidence reveals the significance of HuD in non–neuronal systems including certain types of cancer cells or endocrine cells in the lung, pancreas, and adrenal gland. In addition, the abnormal function of HuD suggests its pathological association with neurological disorders, cancers, and diabetes. Thus, this review discusses HuD–mediated gene regulation in neuronal and non–neuronal systems to address how it works to orchestrate gene expression and how its expression is controlled in the stress response of pathogenesis of diseases. ABSTRACT: HuD (also known as ELAVL4) is an RNA–binding protein belonging to the human antigen (Hu) family that regulates stability, translation, splicing, and adenylation of target mRNAs. Unlike ubiquitously distributed HuR, HuD is only expressed in certain types of tissues, mainly in neuronal systems. Numerous studies have shown that HuD plays essential roles in neuronal development, differentiation, neurogenesis, dendritic maturation, neural plasticity, and synaptic transmission by regulating the metabolism of target mRNAs. However, growing evidence suggests that HuD also functions as a pivotal regulator of gene expression in non–neuronal systems and its malfunction is implicated in disease pathogenesis. Comprehensive knowledge of HuD expression, abundance, molecular targets, and regulatory mechanisms will broaden our understanding of its role as a versatile regulator of gene expression, thus enabling novel treatments for diseases with aberrant HuD expression. This review focuses on recent advances investigating the emerging role of HuD, its molecular mechanisms of target gene regulation, and its disease relevance in both neuronal and non–neuronal systems.