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      Alpha-alumina nanoparticles induce efficient autophagy-dependent cross-presentation and potent antitumour response

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      1 , 2 , 1 , 2
      Nature nanotechnology

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          Abstract

          Therapeutic cancer vaccination is an attractive immune therapy strategy to actively induce T cells that specifically recognize and kill tumour cells in cancer patients. However, it remains difficult to generate a large number antigen-specific T cells using conventional vaccine carrier systems 1, 2 . Here we show that α-Al 2O 3 nanoparticles can act as an antigen carrier to reduce the amount of antigen required by dendritic cells to activate T cells in vitro and in vivo. We found that α- Al 2O 3 nanoparticles delivered antigens to autophagosomes in dendritic cells (DCs), which then presented the antigens to T cells through autophagy – the normal degradation process of cell components in cells. Immunization of mice with α-Al 2O 3 nanoparticles that are conjugated to either a model tumour antigen or autophagosomes derived from tumour cells resulted in tumour regression. These results suggest that α-Al 2O 3 nanoparticles may be a promising adjuvant in the development of therapeutic cancer vaccines.

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          Most cited references21

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          A role for ubiquitin in selective autophagy.

          Ubiquitination is the hallmark of protein degradation by the 26S proteasome. However, the proteasome is limited in its capacity to degrade oligomeric and aggregated proteins. Removal of harmful protein aggregates is mediated by autophagy, a mechanism by which the cell sequesters cytosolic cargo and delivers it for degradation by the lysosome. Identification of autophagy receptors, such as p62/SQSTM1 and NBR1, which simultaneously bind both ubiquitin and autophagy-specific ubiquitin-like modifiers, LC3/GABARAP, has provided a molecular link between ubiquitination and autophagy. This review explores the hypothesis that ubiquitin represents a selective degradation signal suitable for targeting various types of cargo, ranging from protein aggregates to membrane-bound organelles and microbes.
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            Discovery of Atg5/Atg7-independent alternative macroautophagy.

            Macroautophagy is a process that leads to the bulk degradation of subcellular constituents by producing autophagosomes/autolysosomes. It is believed that Atg5 (ref. 4) and Atg7 (ref. 5) are essential genes for mammalian macroautophagy. Here we show, however, that mouse cells lacking Atg5 or Atg7 can still form autophagosomes/autolysosomes and perform autophagy-mediated protein degradation when subjected to certain stressors. Although lipidation of the microtubule-associated protein light chain 3 (LC3, also known as Map1lc3a) to form LC3-II is generally considered to be a good indicator of macroautophagy, it did not occur during the Atg5/Atg7-independent alternative process of macroautophagy. We also found that this alternative process of macroautophagy was regulated by several autophagic proteins, including Unc-51-like kinase 1 (Ulk1) and beclin 1. Unlike conventional macroautophagy, autophagosomes seemed to be generated in a Rab9-dependent manner by the fusion of isolation membranes with vesicles derived from the trans-Golgi and late endosomes. In vivo, Atg5-independent alternative macroautophagy was detected in several embryonic tissues. It also had a function in clearing mitochondria during erythroid maturation. These results indicate that mammalian macroautophagy can occur through at least two different pathways: an Atg5/Atg7-dependent conventional pathway and an Atg5/Atg7-independent alternative pathway.
              • Record: found
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              Towards an understanding of the adjuvant action of aluminium.

              The efficacy of vaccines depends on the presence of an adjuvant in conjunction with the antigen. Of these adjuvants, the ones that contain aluminium, which were first discovered empirically in 1926, are currently the most widely used. However, a detailed understanding of their mechanism of action has only started to be revealed. In this Timeline article, we briefly describe the initial discovery of aluminium adjuvants and discuss historically important advances. We also summarize recent progress in the field and discuss their implications and the remaining questions on how these adjuvants work.

                Author and article information

                Journal
                101283273
                34218
                Nat Nanotechnol
                Nat Nanotechnol
                Nature nanotechnology
                1748-3387
                1748-3395
                18 August 2011
                18 September 2011
                30 October 2012
                : 6
                : 10
                : 645-650
                Affiliations
                [1 ]Department of Physics, Portland State University, Portland, Oregon, USA
                [2 ]Laboratory of Cancer Immunobiology, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon, USA
                Author notes
                Article
                NIHMS319153
                10.1038/nnano.2011.153
                3483867
                21926980
                c4932e8a-7fea-4813-8a1c-f56019bc5c7f

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: National Cancer Institute : NCI
                Award ID: R21 CA141278-02 || CA
                Funded by: National Cancer Institute : NCI
                Award ID: R21 CA141278-01 || CA
                Funded by: National Cancer Institute : NCI
                Award ID: R01 CA107243-05 || CA
                Categories
                Article

                Nanotechnology
                Nanotechnology

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