RNA localization: Making its way to the center stage

Highlights

• RNA localization is a prevalent and functionally important layer of gene regulation.

• A complex network of cis- and trans-regulators modulate RNA trafficking.

• Nuclear history is important for cytoplasmic targeting of mRNAs.

• Several neurological and muscle disorders are associated with alterations in RNA localization.

Abstract

Cells are highly organized entities that rely on intricate addressing mechanisms to sort their constituent molecules to precise subcellular locations. These processes are crucial for cells to maintain their proper organization and carry out specialized functions in the body, consequently genetic perturbations that clog up these addressing systems can contribute to disease aetiology. The trafficking of RNA molecules represents an important layer in the control of cellular organization, a process that is both highly prevalent and for which features of the regulatory machineries have been deeply conserved evolutionarily. RNA localization is commonly driven by trans-regulatory factors, including RNA binding proteins at the core, which recognize specific cis-acting zipcode elements within the RNA transcripts. Here, we first review the functions and biological benefits of intracellular RNA trafficking, from the perspective of both coding and non-coding RNAs. Next, we discuss the molecular mechanisms that modulate this localization, emphasizing the diverse features of the cis- and trans-regulators involved, while also highlighting emerging technologies and resources that will prove instrumental in deciphering RNA targeting pathways. We then discuss recent findings that reveal how co-transcriptional regulatory mechanisms operating in the nucleus can dictate the downstream cytoplasmic localization of RNAs. Finally, we survey the growing number of human diseases in which RNA trafficking pathways are impacted, including spinal muscular atrophy, Alzheimer's disease, fragile X syndrome and myotonic dystrophy. Such examples highlight the need to further dissect RNA localization mechanisms, which could ultimately pave the way for the development of RNA-oriented diagnostic and therapeutic strategies. This article is part of a Special Issue entitled "Biochemistry of Synthetic Biology - Recent Developments" Guest Editor: Dr. Ilka Heinemann and Dr. Patrick O’Donoghue.

Introduction

The control of gene expression in eukaryotes is orchestrated by a variety of regulatory steps operating at different points during the life cycle of an RNA, from transcription initiation to downstream maturation events that will ultimately influence the processing, stability, localization and, in the case of mRNAs, translation of the message into protein (Fig. 1). These events are highly intertwined and often take place in different areas of the cell, from sub-regions of the nucleus where RNAs are first synthesized as nascent immature transcripts, and upon maturation, to the far outreaches of the cytoplasm, or even beyond the boundaries of the cell for RNAs that are secreted into the extracellular space. Therefore, not only is the subcellular distribution of RNA molecules key to ensuring the proper coordination of transcript maturation events, it is also crucial in modulating the cellular functions of the various classes of coding and non-coding RNAs transcribed from the genome. Transcript localization is thought to be a highly regulated process, modulated by specific cis-acting zipcode elements and trans-acting RNA binding proteins (RBPs) that seed the assembly of ribonucleoprotein (RNP) complexes on the target RNA, ultimately dictating its cellular fate.

In this review, we begin by discussing the established biological and cellular functions of RNA localization. We then examine the general principles of transcript localization at the molecular level, focusing on cis- and trans-regulatory elements, while highlighting emerging technologies and resources that will be key to mapping RNA localization pathways. Although a few general modes of RNA trafficking have been delineated thus far, many additional steps are involved in coupling localization control with other aspects of post-transcriptional regulation between the nucleus and cytoplasm. Therefore, we further elaborate on the concepts of co-transcriptional recruitment of localization determinants at the level of gene promoter regions, and ties to processes that follow thereafter, such as splicing and various events in the cytoplasm, including coordination of translational repression and localized translation. Finally, we discuss the growing number of diseases that have been associated with defects in RNA trafficking, which further underline the need to dissect RNA localization pathways and to devise strategies to manipulate them therapeutically.