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.

无意义介导的mRNA衰减（NMD）是一种转录后质量控制机制，可消除细胞中异常的转录本。可通过翻译核糖体，eRF和导致其降解的反式NMD因子来识别异常的转录本。该反式因子在真核生物中是保守的，由UPF1，UPF2和UPF3蛋白组成。有趣的是，在人类中，UPF3作为旁系同源蛋白，UPF3A和UPF3B存在。虽然传统上已知UPF3旁系同源物参与NMD途径，但越来越多的共识认为，除了质量控制以外，UPF3蛋白质还决定了其他关键细胞功能。这篇综述介绍了有关UPF3旁系同源物在不同细胞过程中的生化功能的当前知识，包括NMD，翻译和遗传补偿反应。我们还讨论了UPF3旁系同源物在中枢神经系统和生殖细胞的发育和功能中的作用。此外，过去十年的重大进展为UPF3旁系同源物在神经发育疾病中的意义提供了新的观点。在这方面，对患者样品进行全基因组和转录组范围的测序分析表明，UPF3B的丢失与脑部疾病（例如智力残疾，自闭症，注意力不足过动症和精神分裂症）有关。因此，我们进一步旨在提供与脑功能丧失突变相关的脑部疾病的见解。UPF3B。