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What is the Human Vault Particle?

Human vaults  are intracellular ribonucleoprotein particle complexes which consists of a major vault protein (MVP), the outer shell, which houses two minor vault proteins (VPARP and TEP1), and several small untranslated RNA molecules.  Naturally occurring human vault particles are ubiquitous and present in every human cell and are the most abundant cytoplasmic protein particle in human cells, 10,000 plus particles per human cell.  They are highly stable inside the cytoplasm and no function is known inside the cell.  Vaults are highly conserved evolutionarily and almost ubiquitously expressed in eukaryotes.  Vaults form a large nanocapsule with a barrel-shaped morphology surrounding a large hollow interior. Evidence suggest that they are an early alert signal to the immune system once a cell is lysed and vaults are released into the intracellular space where they are rapidly engulfed by APCs.

Vault Technology Platform

Vault Pharma is developing safe and effective therapies based upon the Vault Technology Platform. Discovered by founder Leonard Rome in 1986, vaults are multi-subunit protein containers that exist in every cell of most animals on the planet. Vault proteins are highly conserved between species. Like viruses, vaults are composed from simple protein subunits and have a large internal cavity. Further, vaults can be engineered to contain exogenous materials (proteins, cytokines, antigens etc.). Ubiquitous throughout the human body, vaults are bio-invisible to the human immune system. This makes vault technology a perfect delivery platform unlike viruses and most synthetic drug delivery technologies that have serious safety complications.

Vaults have been extensively studied and after a decade of engineering are now ready for commercialization. By understanding the native human vault structure, The Rome laboratory has discovered a region known as the INT packaging domain. This domain, a peptide motif found on the native vault enzyme VPARP,  has an extremely high affinity for the inside of the vault particle. By engineering the INT domain together with therapeutics, vaults can package these active agents  inside and become a therapeutic delivery platform. Payloads attached to INT are pharmaceutically active and therefore offer a flexible and safe platform that can be used to develop a portfolio of multiple vault-medicines quickly and cost effectively.

Vault Structure & Engineering

The vault particle is formed from 78 copies of the major vault protein (MVP) which contains domains/areas that make a recombinant Vault easily customizable. We use two different strategies for packaging therapeutics inside vaults

Vault Targeting

Vaults can be modified for specific targeting.

The C-domain of MVP is found outside of the assembled vault particle. This domain can be used for targeting to specific cells by attaching specific cell-surface antibodies. By coding the c-terminus of the major vault protein with a high affinity Fc binding domain, vaults can be modified with specific target antibodies. Targeted vaults are then able to deliver their drug to specific destinations in the body such as cancerous tissue or antigen presenting cells of the immune system. These features make recombinant vaults an ideal platform for therapeutic delivery

Vaults in the Scientific Literature

Vault Publications from the Rome Laboratory at UCLA (1986-2015)

  1. Wang M, Abad D, Kickhoefer VA, Rome LH, Mahendra S. Vault Nanoparticles Packaged with Enzymes as an Efficient Pollutant Biodegradation Technology. ACS nano. 2015; 9(11):10931-40. PMID: 26493711
  1. Matsumoto NM, Buchman GW, Rome LH, Maynard HD. Dual pH- and Temperature-Responsive Protein Nanoparticles. European polymer journal. 2015; 69:532-539. PMID: 26365998, PMCID: PMC4565796
  1. Zhu Y, Jiang J, Said-Sadier N, Boxx G, Champion C, et al. Activation of the NLRP3 inflammasome by vault nanoparticles expressing a chlamydial epitope. Vaccine. 2015; 33(2):298-306. PMID: 25448112, PMCID: PMC4272900
  1. Mrazek J, Toso D, Ryazantsev S, Zhang X, Zhou ZH, et al. Polyribosomes are molecular 3D nanoprinters that orchestrate the assembly of vault particles. ACS nano. 2014; 8(11):11552-9. PMID: 25354757, PMCID: PMC4245718
  1. Buehler DC, Marsden MD, Shen S, Toso DB, Wu X, et al. Bioengineered vaults: self-assembling protein shell-lipophilic core nanoparticles for drug delivery. ACS nano. 2014; 8(8):7723-32. PMID: 25061969, PMCID: PMC4148163
  1. Rome LH, Kickhoefer VA. Development of the vault particle as a platform technology. ACS nano. 2013; 7(2):889-902. PMID: 23267674
  1. Matsumoto NM, Prabhakaran P, Rome LH, Maynard HD. Smart vaults: thermally-responsive protein nanocapsules. ACS nano. 2013; 7(1):867-74. PMID: 23259767, PMCID: PMC3991814
  1. Yang J, Srinivasan A, Sun Y, Mrazek J, Shu Z, et al. Vault nanoparticles engineered with the protein transduction domain, TAT48, enhances cellular uptake. Integrative biology : quantitative biosciences from nano to macro. 2013; 5(1):151-8. PMID: 22785558, PMCID: PMC3704152
  1. Sharma S, Zhu L, Srivastava MK, Harris-White M, Huang M, et al. CCL21 Chemokine Therapy for Lung Cancer. International trends in immunity. 2013; 1(1):10-15. PMID: 25264541, PMCID: PMC4175527
  1. Kar UK, Jiang J, Champion CI, Salehi S, Srivastava M, et al. Vault nanocapsules as adjuvants favor cell-mediated over antibody-mediated immune responses following immunization of mice. PloS one. 2012; 7(7):e38553.PMID: 22808011, PMCID: PMC3394761
  1. Han M, Kickhoefer VA, Nemerow GR, Rome LH. Targeted vault nanoparticles engineered with an endosomolytic peptide deliver biomolecules to the cytoplasm. ACS nano. 2011; 5(8):6128-37. PMID: 21740042, PMCID: PMC3163598
  1. Buehler DC, Toso DB, Kickhoefer VA, Zhou ZH, Rome LH. Vaults engineered for hydrophobic drug delivery. Small (Weinheim an der Bergstrasse, Germany). 2011; 7(10):1432-9. PMID: 21506266, PMCID: PMC4182016
  1. Kar UK, Srivastava MK, Andersson A, Baratelli F, Huang M, et al. Novel CCL21-vault nanocapsule intratumoral delivery inhibits lung cancer growth. PloS one. 2011; 6(5):e18758. PMID: 21559281, PMCID: PMC3086906
  1. Yang J, Kickhoefer VA, Ng BC, Gopal A, Bentolila LA, et al. Vaults are dynamically unconstrained cytoplasmic nanoparticles capable of half vault exchange. ACS nano. 2010; 4(12):7229-40. PMID: 21121616, PMCID: PMC3020078
  1. Xia Y, Ramgopal Y, Li H, Shang L, Srinivas P, et al. Immobilization of recombinant vault nanoparticles on solid substrates. ACS nano. 2010; 4(3):1417-24. PMID: 20146454
  1. Goldsmith LE, Pupols M, Kickhoefer VA, Rome LH, Monbouquette HG. Utilization of a protein “shuttle” to load vault nanocapsules with gold probes and proteins. ACS nano. 2009; 3(10):3175-83. PMID: 19775119
  1. Esfandiary R, Kickhoefer VA, Rome LH, Joshi SB, Middaugh CR. Structural stability of vault particles. Journal of pharmaceutical sciences. 2009; 98(4):1376-86. PMID: 18683860
  1. Lai CY, Wiethoff CM, Kickhoefer VA, Rome LH, Nemerow GR. Vault nanoparticles containing an adenovirus-derived membrane lytic protein facilitate toxin and gene transfer. ACS nano. 2009; 3(3):691-9. PMID: 19226129, PMCID: PMC2707358
  1. Kickhoefer VA, Han M, Raval-Fernandes S, Poderycki MJ, Moniz RJ, et al. Targeting vault nanoparticles to specific cell surface receptors. ACS nano. 2009; 3(1):27-36. PMID: 19206245, PMCID: PMC2641028
  1. Champion CI, Kickhoefer VA, Liu G, Moniz RJ, Freed AS, et al. A vault nanoparticle vaccine induces protective mucosal immunity. PloS one. 2009; 4(4):e5409. PMID: 19404403, PMCID: PMC2671841
  1. Yu M, Ng BC, Rome LH, Tolbert SH, Monbouquette HG. Reversible pH lability of cross-linked vault nanocapsules. Nano letters. 2008; 8(10):3510-5. PMID: 18803423, PMCID: PMC3046048
  1. Ng BC, Yu M, Gopal A, Rome LH, Monbouquette HG, et al. Encapsulation of semiconducting polymers in vault protein cages. Nano letters. 2008; 8(10):3503-9. PMID: 18803422, PMCID: PMC3046045
  1. Xia T, Rome L, Nel A. Nanobiology: particles slip cell security. Nature materials. 2008; 7(7):519-20. PMID: 18574478
  1. Anderson DH, Kickhoefer VA, Sievers SA, Rome LH, Eisenberg D. Draft crystal structure of the vault shell at 9-A resolution. PLoS biology. 2007; 5(11):e318. PMID: 18044992, PMCID: PMC2229873
  1. Kaddis CS, Lomeli SH, Yin S, Berhane B, Apostol MI, et al. Sizing large proteins and protein complexes by electrospray ionization mass spectrometry and ion mobility. Journal of the American Society for Mass Spectrometry. 2007; 18(7):1206-16. PMID: 17434746, PMCID: PMC2680693
  1. Goldsmith LE, Yu M, Rome LH, Monbouquette HG. Vault nanocapsule dissociation into halves triggered at low pH. Biochemistry. 2007; 46(10):2865-75. PMID: 17302392
  1. Poderycki MJ, Kickhoefer VA, Kaddis CS, Raval-Fernandes S, Johansson E, et al. The vault exterior shell is a dynamic structure that allows incorporation of vault-associated proteins into its interior. Biochemistry. 2006; 45(39):12184-93. PMID: 17002318, PMCID: PMC2538551
  1. Slesina M, Inman EM, Moore AE, Goldhaber JI, Rome LH, et al. Movement of vault particles visualized by GFP-tagged major vault protein. Cell and tissue research. 2006; 324(3):403-10. PMID: 16505994
  1. Raval-Fernandes S, Kickhoefer VA, Kitchen C, Rome LH. Increased susceptibility of vault poly(ADP-ribose) polymerase-deficient mice to carcinogen-induced tumorigenesis. Cancer research. 2005; 65(19):8846-52. PMID: 16204055
  1. Slesina M, Inman EM, Rome LH, Volknandt W. Nuclear localization of the major vault protein in U373 cells. Cell and tissue research. 2005; 321(1):97-104. PMID: 15902504
  1. Kickhoefer VA, Garcia Y, Mikyas Y, Johansson E, Zhou JC, et al. Engineering of vault nanocapsules with enzymatic and fluorescent properties. Proceedings of the National Academy of Sciences of the United States of America. 2005; 102(12):4348-52. PMID: 15753293, PMCID: PMC555531
  1. Poderycki MJ, Rome LH, Harrington L, Kickhoefer VA. The p80 homology region of TEP1 is sufficient for its association with the telomerase and vault RNAs, and the vault particle. Nucleic acids research. 2005; 33(3):893-902. PMID: 15701761, PMCID: PMC549401
  1. Mikyas Y, Makabi M, Raval-Fernandes S, Harrington L, Kickhoefer VA, et al. Cryoelectron microscopy imaging of recombinant and tissue derived vaults: localization of the MVP N termini and VPARP. Journal of molecular biology. 2004; 344(1):91-105. PMID: 15504404
  1. Liu Y, Snow BE, Kickhoefer VA, Erdmann N, Zhou W, et al. Vault poly(ADP-ribose) polymerase is associated with mammalian telomerase and is dispensable for telomerase function and vault structure in vivo. Molecular and cellular biology. 2004; 24(12):5314-23. PMID: 15169895, PMCID: PMC419898
  1. Emre N, Raval-Fernandes S, Kickhoefer VA, Rome LH. Analysis of MVP and VPARP promoters indicates a role for chromatin remodeling in the regulation of MVP. Biochimica et biophysica acta. 2004; 1678(1):33-46. PMID: 15093136
  1. Kickhoefer VA, Emre N, Stephen AG, Poderycki MJ, Rome LH. Identification of conserved vault RNA expression elements and a non-expressed mouse vault RNA gene. Gene. 2003; 309(2):65-70. PMID: 12758122
  1. Kickhoefer VA, Poderycki MJ, Chan EK, Rome LH. The La RNA-binding protein interacts with the vault RNA and is a vault-associated protein. The Journal of biological chemistry. 2002; 277(43):41282-6. PMID: 12196535
  1. Hu Y, Stephen AG, Cao J, Tanzer LR, Slapak CA, et al. A very early induction of major vault protein accompanied by increased drug resistance in U-937 cells. International journal of cancer. 2002; 97(2):149-56. PMID:11774257
  1. Stephen AG, Raval-Fernandes S, Huynh T, Torres M, Kickhoefer VA, et al. Assembly of vault-like particles in insect cells expressing only the major vault protein. The Journal of biological chemistry. 2001; 276(26):23217-20. PMID: 11349122
  1. Siva AC, Raval-Fernandes S, Stephen AG, LaFemina MJ, Scheper RJ, et al. Up-regulation of vaults may be necessary but not sufficient for multidrug resistance. International journal of cancer. 2001; 92(2):195-202. PMID: 11291045
  1. Kickhoefer VA, Liu Y, Kong LB, Snow BE, Stewart PL, et al. The Telomerase/vault-associated protein TEP1 is required for vault RNA stability and its association with the vault particle. The Journal of cell biology. 2001; 152(1):157-64. PMID: 11149928, PMCID: PMC2193651
  1. Kong LB, Siva AC, Kickhoefer VA, Rome LH, Stewart PL. RNA location and modeling of a WD40 repeat domain within the vault. RNA (New York, N.Y.). 2000; 6(6):890-900. PMID: 10864046, PMCID: PMC1369965
  1. Schroeijers AB, Siva AC, Scheffer GL, de Jong MC, Bolick SC, et al. The Mr 193,000 vault protein is up-regulated in multidrug-resistant cancer cell lines. Cancer research. 2000; 60(4):1104-10. PMID: 10706131
  1. Kickhoefer VA, Stephen AG, Harrington L, Robinson MO, Rome LH. Vaults and telomerase share a common subunit, TEP1. The Journal of biological chemistry. 1999; 274(46):32712-7. PMID: 10551828
  1. Kickhoefer VA, Siva AC, Kedersha NL, Inman EM, Ruland C, et al. The 193-kD vault protein, VPARP, is a novel poly(ADP-ribose) polymerase. The Journal of cell biology. 1999; 146(5):917-28. PMID: 10477748, PMCID: PMC2169495
  1. Kong LB, Siva AC, Rome LH, Stewart PL. Structure of the vault, a ubiquitous celular component. Structure (London, England : 1993). 1999; 7(4):371-9. PMID: 10196123
  1. Herrmann C, Golkaramnay E, Inman E, Rome L, Volknandt W. Recombinant major vault protein is targeted to neuritic tips of PC12 cells. The Journal of cell biology. 1999; 144(6):1163-72. PMID: 10087261, PMCID: PMC2150576
  1. Kickhoefer VA, Rajavel KS, Scheffer GL, Dalton WS, Scheper RJ, et al. Vaults are up-regulated in multidrug-resistant cancer cell lines. The Journal of biological chemistry. 1998; 273(15):8971-4. PMID: 9535882
  1. Kickhoefer VA, Vasu SK, Rome LH. Vaults are the answer, what is the question? Trends in cell biology. 1996; 6(5):174-8. PMID: 15157468
  1. Izquierdo MA, Scheffer GL, Flens MJ, Shoemaker RH, Rome LH, et al. Relationship of LRP-human major vault protein to in vitro and clinical resistance to anticancer drugs. Cytotechnology. 1996; 19(3):191-7. PMID: 8862006
  1. Vasu SK, Rome LH. Dictyostelium vaults: disruption of the major proteins reveals growth and morphological defects and uncovers a new associated protein. The Journal of biological chemistry. 1995; 270(28):16588-94. PMID: 7622465
  1. Rome LH. Multidrug resistance: locked in the vault? Nature medicine. 1995; 1(6):527. PMID: 7585117
  1. Kickhoefer VA, Rome LH. The sequence of a cDNA encoding the major vault protein from Rattus norvegicus. Gene. 1994; 151(1-2):257-60. PMID: 7828886
  1. Vilalta A, Kickhoefer VA, Rome LH, Johnson DL. The rat vault RNA gene contains a unique RNA polymerase III promoter composed of both external and internal elements that function synergistically. The Journal of biological chemistry. 1994; 269(47):29752-9. PMID: 7525587
  1. Chugani DC, Rome LH, Kedersha NL. Evidence that vault ribonucleoprotein particles localize to the nuclear pore complex. Journal of cell science. 1993; 106 ( Pt 1):23-9. PMID: 8270627
  1. Vasu SK, Kedersha NL, Rome LH. cDNA cloning and disruption of the major vault protein alpha gene (mvpA) in Dictyostelium discoideum. The Journal of biological chemistry. 1993; 268(21):15356-60. PMID: 8340365
  1. Kickhoefer VA, Searles RP, Kedersha NL, Garber ME, Johnson DL, et al. Vault ribonucleoprotein particles from rat and bullfrog contain a related small RNA that is transcribed by RNA polymerase III. The Journal of biological chemistry. 1993; 268(11):7868-73. PMID: 7681830
  1. Rome L, Kedersha N, Chugani D. Unlocking vaults: organelles in search of a function. Trends in cell biology. 1991; 1(2-3):47-50. PMID: 14731565
  1. Kedersha NL, Heuser JE, Chugani DC, Rome LH. Vaults. III. Vault ribonucleoprotein particles open into flower-like structures with octagonal symmetry. The Journal of cell biology. 1991; 112(2):225-35. PMID: 1988458, PMCID: PMC2288824
  1. Chugani DC, Kedersha NL, Rome LH. Vault immunofluorescence in the brain: new insights regarding the origin of microglia. The Journal of neuroscience : the official journal of the Society for Neuroscience. 1991; 11(1):256-68. PMID: 1986066
  1. Kedersha NL, Miquel MC, Bittner D, Rome LH. Vaults. II. Ribonucleoprotein structures are highly conserved among higher and lower eukaryotes. The Journal of cell biology. 1990; 110(4):895-901. PMID: 1691193, PMCID: PMC2116106
  1. Kedersha NL, Rome LH. Vaults: large cytoplasmic RNP’s that associate with cytoskeletal elements. Molecular biology reports. 1990; 14(2-3):121-2. PMID: 1694556
  1. Kedersha NL, Rome LH. Isolation and characterization of a novel ribonucleoprotein particle: large structures contain a single species of small RNA. The Journal of cell biology. 1986; 103(3):699-709. PMID: 2943744, PMCID: PMC2114306
  1. Kedersha NL, Rome LH. Preparative agarose gel electrophoresis for the purification of small organelles and particles. Analytical biochemistry. 1986; 156(1):161-70. PMID: 2426986
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