Functional roles of human Up-frameshift suppressor 3 (UPF3) proteins: From nonsense-mediated mRNA decay to neurodevelopmental disorders

Highlights

• The versatile functions of UPF3 paralogs in cellular processes are described.

• The probable roles of UPF3 paralogs in the progression of X-linked intellectual disability are covered.

• UPF3 paralogs are crucial for many developmental processes.

Abstract

Nonsense-mediated mRNA decay (NMD) is a post-transcriptional quality control mechanism that eradicates aberrant transcripts from cells. Aberrant transcripts are recognized by translating ribosomes, eRFs, and trans-acting NMD factors leading to their degradation. The trans-factors are conserved among eukaryotes and consist of UPF1, UPF2, and UPF3 proteins. Intriguingly, in humans, UPF3 exists as paralog proteins, UPF3A, and UPF3B. While UPF3 paralogs are traditionally known to be involved in the NMD pathway, there is a growing consensus that there are other critical cellular functions beyond quality control that are dictated by the UPF3 proteins. This review presents the current knowledge on the biochemical functions of UPF3 paralogs in diverse cellular processes, including NMD, translation, and genetic compensation response. We also discuss the contribution of the UPF3 paralogs in development and function of the central nervous system and germ cells. Furthermore, significant advances in the past decade have provided new perspectives on the implications of UPF3 paralogs in neurodevelopmental diseases. In this regard, genome- and transcriptome-wide sequencing analysis of patient samples revealed that loss of UPF3B is associated with brain disorders such as intellectual disability, autism, attention deficit hyperactivity disorder, and schizophrenia. Therefore, we further aim to provide an insight into the brain diseases associated with loss-of-function mutations of UPF3B.

Introduction

Nonsense-mediated mRNA decay (NMD) is a highly specialized surveillance pathway that barricades the building of aberrant transcripts in the cytoplasm. NMD safeguards cells from the deleterious effects of premature termination codon (PTC)-containing transcripts which, otherwise, get translated into potentially toxic truncated proteins. Besides PTC, other cis-acting features (NMD-inducing features) that might elicit NMD include mRNAs with long 3′ untranslated region (3′UTR) [1,2], introns in 3′UTR, or an upstream open reading frame (uORF) [3]. Nevertheless, the presence of these canonical determinants on an mRNA do not always trigger NMD. In this regard, many mRNAs harbor NMD-inhibitory sequences such as AU-rich sequences and RNA stability element (RSE), which evade NMD [4,5]. These suggest the intricate nature of NMD in choosing its substrate.

Besides the primary role of NMD in mRNA quality control, NMD also regulates the expression of normal mRNAs and maintains cellular homeostasis. Since organism development is highly dependent on the spatial and temporal synchronization of gene expression, NMD plays a vital role in controlling this dynamic process by regulating the mRNA decay rate [6]. Accordingly, NMD is associated with many physiological or pathophysiological conditions, as described in detail in recent reviews [[7], [8], [9], [10]]. Over the last decade, studies on NMD in humans have increased due to its impact on genetic disorders, including cancer and neuropathological conditions [11,12].

For recognition and efficient degradation of aberrant transcripts, the NMD factors associate with the exon junction complex (EJC). During splicing, the spliceosome deposits a multiprotein complex termed EJC onto mRNAs at a distance of 24 nt upstream of an exon-exon junction [[13], [14], [15]]. The subunits that form the core EJC are DEAD-box RNA helicase eIF4AIII and MAGOH-Y14 heterodimer [16,17]. CASC3 was previously regarded as the fourth EJC core protein, but recent studies showed that CASC3 functions during the late phase of the EJC life cycle (reviewed in Ref. [18]). The core EJC aids in nucleating the peripheral EJC factors through dynamic interactions and thereby regulates various post-transcriptional events. Some well known peripheral EJC proteins and complexes are the splicing regulatory complexes, ASAP (ACIN1-RNPS1-SAP18), and PSAP (PNN-RNPS1-SAP18), the transcription export complex (TREX), and the NMD factor UPF3B (Up-frameshift suppressor 3 homolog B) (reviewed in Ref. [[18], [19], [20]]). EJC acts as a molecular link between splicing and NMD by serving as a platform for assembly of the NMD factors [21,22].

In humans, NMD factors include the up-frameshift proteins UPF1, UPF2, and UPF3B and the suppressor with morphogenetic effect on genitalia proteins SMG1, SMG5, SMG6, SMG7, SMG8, and SMG9 [12]. Among the three UPF proteins, UPF3B is particularly interesting in having a sister protein, UPF3A. In this review, we discuss biochemical functions and biology of the UPF3 paralogs in various cellular processes. We also discuss the brain disorders associated with UPF3B mutations and review the current perspective on the role of UPF3B in neurodevelopment.