Abstract
Simple SummaryIn recent decades, a molecular complex referred to as vault nanoparticle has attracted much attention by the scientific community, due to its unique properties. At the molecular scale, it is a huge assembly consisting of 78 97-kDa polypeptide chains enclosing an internal cavity, wherein enzymes involved in DNA integrity maintenance and some small noncoding RNAs are accommodated. Basically, two reasons justify this interest. On the one hand, this complex represents an ideal tool for the targeted delivery of drugs, provided it is suitably engineered, either chemically or genetically; on the other hand, it has been shown to be involved in several cellular pathways and mechanisms that most often result in multidrug resistance. It is therefore expected that a better understanding of the physiological roles of this ribonucleoproteic complex may help develop new therapeutic strategies capable of coping with cancer progression. Here, we provide a comprehensive review of the current knowledge.The vault nanoparticle is a eukaryotic ribonucleoprotein complex consisting of 78 individual 97 kDa-“major vault protein” (MVP) molecules that form two symmetrical, cup-shaped, hollow halves. It has a huge size (72.5 × 41 × 41 nm) and an internal cavity, wherein the vault poly(ADP-ribose) polymerase (vPARP), telomerase-associated protein-1 (TEP1), and some small untranslated RNAs are accommodated. Plenty of literature reports on the biological role(s) of this nanocomplex, as well as its involvement in diseases, mostly oncological ones. Nevertheless, much has still to be understood as to how vault participates in normal and pathological mechanisms. In this comprehensive review, current understanding of its biological roles is discussed. By different mechanisms, vault’s individual components are involved in major cellular phenomena, which result in protection against cellular stresses, such as DNA-damaging agents, irradiation, hypoxia, hyperosmotic, and oxidative conditions. These diverse cellular functions are accomplished by different mechanisms, mainly gene expression reprogramming, activation of proliferative/prosurvival signaling pathways, export from the nucleus of DNA-damaging drugs, and import of specific proteins. The cellular functions of this nanocomplex may also result in the onset of pathological conditions, mainly (but not exclusively) tumor proliferation and multidrug resistance. The current understanding of its biological roles in physiological and pathological processes should also provide new hints to extend the scope of its exploitation as a nanocarrier for drug delivery.
Highlights
The vault nanoparticle was first discovered in 1986 as a contaminant of rat liver coated vesicles [1]
The most reliable figure is probably around nine [30], but it cannot be excluded that it may vary depending on the physiological conditions, in keeping with the observations that vault poly(ADP-ribose) polymerase (vPARP) is only partially associated with vaults and is found in the nucleus, in the cytoplasm, and in the mitotic spindle during mitosis [6,31]
Kinase (MAPK) is under control of a wide repertoire of receptor tyrosine kinases (RTKs), including several growth factors [90], which regulate cell proliferation. These results have suggested a model whereby Bcl2associated athanogene 3 (BAG3) mediates major vault protein (MVP) accumulation in the nucleus in association with ERK1/2, which results in activation of the latter and the ensuing prosurvival action
Summary
The vault nanoparticle was first discovered in 1986 as a contaminant of rat liver coated vesicles [1]. Plenty of investigations provided detailed structural characterizations and led to the identification of its molecular components It was dubbed vault as its morphology is reminiscent of the ceilings of ancient cathedrals. A singular trait of the vault nanoparticle is the way it assembles, as it was shown that biosynthesis and assembling of MVP subunits take place sequentially at the level of polyribosomes, which act similar to a 3D nanoprinter [15] It is worth mentioning its dynamic nature, as it can exchange individual MVP subunits in vivo, as well as separate at the particle waist and reassemble, reconstituting the whole vault. We present a comprehensive review, mainly focusing on the current knowledge of their roles in major cellular phenomena, such as signal transduction, control of gene expression, apoptosis, as well as in their dysregulation and the resulting onset of pathological conditions
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