Vps4b, short for vacuolar protein sorting 4B, is a member of the ATPase associated with diverse cellular activities (AAA) protein family. It is a component of the endosomal sorting complexes required for transport machinery, regulating the internalization and lysosomal degradation of membrane proteins, and is involved in protein degradation and cell membrane fusion [1,2].

In gene knockout studies, homozygous deletion of the Vps4b gene in mice led to early embryonic lethality at approximately embryonic day 9.5 (E9.5), while heterozygous knockout mice developed normally and were fertile [1]. In vitro cell experiments showed that Vps4b influenced the proliferation, apoptosis, and cell cycle of transfected human neuroblastoma cells. Also, in RNA interference-mediated knockdown of Vps4b in these cells and in Vps4b+/- E12.5 embryos, the mRNA expression levels of apoptosis-, cell cycle-, and endocytosis-related genes were significantly regulated, suggesting signal transduction disorders of cell endocytosis contribute to the prenatal lethality of Vps4b-/- mice [1].

Vps4b heterozygous mice did not develop tooth defects replicating human dentin dysplasia I, likely due to species differences in tooth development [2]. A Vps4b mutation in dental follicle cells from a dentin dysplasia type I patient impaired osteogenic differentiation, downregulating osteoblast-related genes [3].

In pancreatic cancer, inactivation of Vps4b impaired autophagy, increasing susceptibility to CD8+ T cell-mediated killing [4]. In venous malformation endothelial cells, downregulated Vps4b, resulting from abnormally activated AKT signaling, contributed to the increased size of small extracellular vesicles [5]. In colorectal cancer, the Vps4b gene is frequently deleted, and its synthetic lethality with Vps4A triggered an inflammatory response [6].

In summary, Vps4b is crucial for normal embryonic development, and its dysfunction is associated with multiple disease conditions such as embryonic lethality, dentin dysplasia, pancreatic cancer, venous malformations, and colorectal cancer. Gene knockout mouse models have been instrumental in revealing these associations, helping us understand the role of Vps4b in specific biological processes and disease mechanisms.