Functional roles of human Up-frameshift suppressor 3 (UPF3) proteins: From nonsense-mediated mRNA decay to neurodevelopmental disorders
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.
Section snippets
Characteristics of UPF3 proteins
In most vertebrates, UPF3 exists as paralog proteins, UPF3A, and UPF3B [23,24]. These paralog proteins are the outcome of gene duplication events during the evolution of vertebrates resulting in a gene pair with differential functions [25]. The paralogs are expressed by two different genes located on distinct chromosomes. The UPF3B gene resides on the X chromosome (previously known as hUpf3p-X) and the UPF3A gene on chromosome 13 (hUpf3p). Nevertheless, the UPF3 paralogs share considerable
Functions and pathological implications of UPF3B
This section discusses the biochemical roles of UPF3B and their physiological significances in neuronal development and neural functions. We also discuss how perturbation in UPF3B expression plays a discernible role in the etiology of various neurodevelopmental disorders. In the next section, we review the functions of the sister paralog, UPF3A. In the closing section, we highlight the importance of the cross-regulatory relationship of UPF3 paralogs.
Dual role of UPF3A in NMD
One of the interesting questions that have concerned researchers was the significance of UPF3 paralog existence in the genome. Hitherto it has been assumed that the UPF3 paralog pair has a redundant function. Consistent with this, it has been shown that tethering of UPF3A to the 3′UTR of a reporter mRNA elicits NMD albeit less efficiently than the strong NMD activity of its sister paralog, UPF3B [24,26]. The findings indicate UPF3A as a weak NMD activator. Subsequently, Chan et al. found that
Comparative functional analysis of UPF3 paralogs
A common aspect between UPF3 paralogs, UPF3A and UPF3B, is that both act as an NMD activator, although a considerable difference exists between their NMD efficiency. Interestingly, the functional redundancy of UPF3 paralogs have implications in neurodevelopmental disorders. Nguyen et al. found that the absence of UPF3B in XLID patients stabilizes the UPF3A protein in patient’s cell lines due to the cross-regulatory relationship of UPF3 paralogs. However, the upregulation of UPF3A protein
Conclusion
NMD is critical for shaping the cellular transcriptome and defining the fate of a cell. The NMD factor UPF3B has intrigued researchers by the presence of its sister protein, UPF3A. The UPF3 paralogs are subject to cross-regulatory response, which inevitably leads to the differential expression pattern of UPF3A and UPF3B. The existence of this conserved cross-regulatory mechanism suggests that tissue-or developmental-stage specific regulation of UPF3 paralogs is critical for organism
Author contributions
Conceptualization and supervision, K.K.S; Resources and Data Curation, B.D. and P.C; Writing-Original Draft, B.D., and P.C; Figures, P.C; Review and Editing, B.D., and K.K.S.
Competing interests
The authors have declared that no competing interests exist.
Declaration of competing interest
We declare no conflict of interest.
Acknowledgment
We thank Dr. Anil M. Limaye and Dr. Preethi Vijayaraj for their constructive criticism and the members of the K.K.S. lab for their helpful comments and suggestions. We are also grateful to five anonymous reviewers for their constructive suggestions on the manuscript. B.D. and P.C. are funded under the scholarships provided by the Ministry of Human Resource Development (MHRD), Govt. of India. K.K.S. acknowledges funding from the Council of Scientific and Industrial Research (CSIR), Government of
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B.D. and P.C. contributed equally to this work.