{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T19:32:55Z","timestamp":1791142375021,"version":"4.1.0"},"reference-count":53,"publisher":"National Academy of Sciences","issue":"35","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2010,8,31]]},"abstract":"<jats:p>\n                    To kill macrophages, the lethal factor component of\n                    <jats:italic>Bacillus anthracis<\/jats:italic>\n                    toxin binds to a carrier protein (PA), which then interacts with the CMG2 receptor protein on the cell surface and is endocytosed into the cytoplasm. CMG2, as well as TEM8, a second PA receptor not present on macrophages, contain a von Willebrand A domain that is crucial for toxin binding. Here we report that integrin \u03b21, another cell surface von Willebrand A domain protein, can mediate and potentiate anthrax toxin endocytosis. By using microarray-based analysis to globally correlate gene expression profiles with toxin sensitivity, we associated toxin effects with the integrin-activating proteins osteopontin and CD44. Further study showed that PA binds to \u03b14\u03b21\u2013 and \u03b15\u03b21\u2013integrin complexes, leading to their conjoint endocytosis, and also interacts\u2014weakly relative to CMG2 but comparably to TEM8\u2014with purified \u03b15\u03b21 complex in vitro. Monoclonal antibody directed against \u03b21-integrin or its \u03b1 integrin partners reduced PA\/integrin endocytosis and anthrax toxin lethality, and hyaluronic acid\u2014which interferes with CD44-mediated integrin activation\u2014had similar effects. Remarkably, whereas deficiency of CMG2 protected macrophages from rapid killing by large toxin doses (&gt;50 ng\/mL), by 24 h the toxin-treated cells were dead. Such late killing of CMG2-deficient cells by high dose toxin as well as the late death observed during exposure of CMG2-producing macrophages to low-dose toxin (&lt;1 ng\/mL), was dependent on integrin function. Effects of inactivating both CMG2 and integrin were synergistic. Collectively, our findings argue strongly that \u03b21-integrin can both potentiate CMG2-mediated endocytosis and serve independently as a low-affinity PA receptor.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1010145107","type":"journal-article","created":{"date-parts":[[2010,8,17]],"date-time":"2010-08-17T00:40:39Z","timestamp":1282005639000},"page":"15583-15588","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":61,"title":["Heterodimeric integrin complexes containing \u03b21-integrin promote internalization and lethality of anthrax toxin"],"prefix":"10.1073","volume":"107","author":[{"given":"Mikhail","family":"Martchenko","sequence":"first","affiliation":[{"name":"Departments of aGenetics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun-Young","family":"Jeong","sequence":"additional","affiliation":[{"name":"Departments of aGenetics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanley N.","family":"Cohen","sequence":"additional","affiliation":[{"name":"Departments of aGenetics and"},{"name":"Medicine, Stanford University School of Medicine, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2010,8,16]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.280.5364.734"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/n35101999"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0431098100"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0407794101"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.12.045"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.065813"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0910782107"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200211018"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2008.01226.x"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1086\/432731"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V65.4.823.823"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M307900200"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0905409106"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)00971-6"},{"key":"e_1_3_3_15_2","first-page":"25","article-title":"Adhesion molecules in hematopoietic cells","volume":"20","author":"Kinashi T","year":"1994","unstructured":"T Kinashi, TA Springer, Adhesion molecules in hematopoietic cells. 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