Ubap2l, also known as NICE-4, is a ubiquitin-and RNA-binding protein highly conserved in metazoans. It is involved in multiple cellular processes such as cell cycle regulation, stem cell activity, stress-response signaling, and is crucial for maintaining cell homeostasis and survival [1]. It also participates in pathways related to nuclear pore complex (NPC) assembly, mitosis, and the formation of stress granules (SGs) and processing bodies (PBs). In addition, it has been associated with oncogenic properties in several human cancers [1].

In human cells, Ubap2l localizes to nuclear pores and is essential for the assembly and stability of properly organized and functional NPCs at the intact nuclear envelope. It facilitates the formation of the Y-complex and its localization to the NE, and promotes the interaction of the Y-complex with critical upstream factors in NPC assembly during interphase [2]. During mitosis, Ubap2l controls both the localization and protein stability of PLK1, an important mitotic regulator. Depletion of Ubap2l leads to severe mitotic defects, increased PLK1 protein levels, and abnormal PLK1 accumulation in mitotic structures [3]. In the context of stress response, Ubap2l is required for both SG assembly and disassembly, and contributes to PB biogenesis and SG-PB interactions [4,5]. In gastric cancer, knockdown of Ubap2l impedes cell migration and invasion, while overexpression enhances these abilities, suggesting its role in cancer metastasis through the PI3K/AKT/SP1/NF-κB axis [6]. Also, de novo likely gene-disruptive variants in Ubap2l in humans are associated with a neurodevelopmental disorder, and Ubap2l haploinsufficiency in mice leads to social and cognitive impairments along with disrupted neurogenesis and reduced SG formation during early brain development [7].

In conclusion, Ubap2l plays diverse and essential biological functions including in NPC homeostasis, mitosis, stress-related granule formation, and cell migration and invasion. Model-based research, especially the use of Ubap2l haploinsufficient mouse models, has revealed its significant contributions to understanding disease mechanisms in areas such as cancer metastasis and neurodevelopmental disorders.