The Antagonistic Gene Paralogs Upf3a and Upf3b Govern Nonsense-Mediated RNA Decay

Abstract

SUMMARY Gene duplication is a major evolutionary force driving adaptation and speciation, as it allows for the acquisition of new functions and can augment or diversify existing functions. Here, we report a gene duplication event that yielded another outcome – the generation of antagonistic functions. One product of this duplication event – UPF3B – is critical for the nonsense-mediated RNA decay (NMD) pathway, while its autosomal counterpart – UPF3A – encodes an enigmatic protein previously shown to have trace NMD activity. Using loss-of-function approaches in vitro and in vivo, we discovered that UPF3A acts primarily as a potent NMD inhibitor that stabilizes hundreds of transcripts. Evidence suggests that UPF3A acquired repressor activity through simple impairment of a critical domain, a rapid mechanism that may have been widely used in evolution. Mice conditionally lacking UPF3A exhibit “hyper” NMD and display defects in embryogenesis and gametogenesis, consistent with UPF3A serving as a molecular rheostat that directs developmental events.

Germ granule-mediated RNA regulation in male germ cells

“…However, although the studies by Shum and coworkers and Bao and coworkers reported the essential role of NMD in spermatogenesis, the importance of CB-localization for the function of these NMD factors remains to be investigated (Bao et al 2016, Shum et al 2016. Important support for the involvement of CB in the NMD pathway comes from a study by Fanourgakis and cowkorkers (Fanourgakis et al 2016).…”

“…However, a massive depletion of both spermatocytes and spermatids was observed, which resulted in the absence of spermatozoa in the epididymis. Interestingly, the deletion of NMD repressor Upf3a, but not Upf3b, led to spermatogenic failure in mice (Shum et al 2016). Therefore, the correct balance between the NMD factors and NMD repressors appears to be important for the proper progression of spermatogenesis.…”

“…Both UPF3A and UPF3B are highly expressed during spermatogenesis. However, while the expression of X-chromosomal UPF3B is downregulated in spermatocytes likely due to the meiotic sex chromosome silencing, the expression of the autosomal UPF3A peaks in these cells (Shum et al 2016). In spermatocytes, where UPF3A is particularly abundantly expressed, the expression of UPF1 and UPF2 is upregulated as well (Bao et al 2016).…”

“…Interestingly, two UPF3 paralogs, UPF3A and UPF3B, were recently shown to have antagonistic roles in NMD. While UPF3B is a potent NMD factor, UPF3A was shown to be a NMD repressor that can sequester UPF2 away from the EJC and the NMD machinery (Shum et al 2016). Both UPF3A and UPF3B are highly expressed during spermatogenesis.…”

“…www.reproduction-online.org Shum et al 2016, MacDonald & Grozdanov 2017 (our unpublished observation). However, although the studies by Shum and coworkers and Bao and coworkers reported the essential role of NMD in spermatogenesis, the importance of CB-localization for the function of these NMD factors remains to be investigated (Bao et al 2016, Shum et al 2016.…”