{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T05:33:44Z","timestamp":1791178424315,"version":"4.1.0"},"reference-count":29,"publisher":"National Academy of Sciences","issue":"33","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2007,8,14]]},"abstract":"<jats:p>\n                    HIV protease inhibitors (HIV-PIs) target the HIV aspartyl protease, which cleaves the HIV gag-pol polyprotein into shorter proteins required for the production of new virions. HIV-PIs are a cornerstone of treatment for HIV but have been associated with lipodystrophy and other side effects. In both human and mouse fibroblasts, we show that HIV-PIs caused an accumulation of prelamin A. The prelamin A in HIV-PI-treated fibroblasts migrated more rapidly than nonfarnesylated prelamin A, comigrating with the farnesylated form of prelamin A that accumulates in ZMPSTE24-deficient fibroblasts. The accumulation of farnesyl-prelamin A in response to HIV-PI treatment was exaggerated in fibroblasts heterozygous for\n                    <jats:italic>Zmpste24<\/jats:italic>\n                    deficiency. HIV-PIs inhibited the endoproteolytic processing of a GFP-prelamin A fusion protein. The HIV-PIs did not affect the farnesylation of HDJ-2, nor did they inhibit protein farnesyltransferase\n                    <jats:italic>in vitro<\/jats:italic>\n                    . HIV-PIs also did not inhibit the activities of the isoprenyl-cysteine carboxyl methyltransferase ICMT or the prenylprotein endoprotease RCE1\n                    <jats:italic>in vitro<\/jats:italic>\n                    , but they did inhibit ZMPSTE24 (IC\n                    <jats:sub>50<\/jats:sub>\n                    : lopinavir, 18.4 \u00b1 4.6 \u03bcM; tipranavir, 1.2 \u00b1 0.4 \u03bcM). We conclude that the HIV-PIs inhibit ZMPSTE24, leading to an accumulation of farnesyl-prelamin A. The inhibition of ZMPSTE24 by HIV-PIs could play a role in the side effects of these drugs.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0704212104","type":"journal-article","created":{"date-parts":[[2007,7,25]],"date-time":"2007-07-25T21:19:07Z","timestamp":1185398347000},"page":"13432-13437","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":125,"title":["HIV protease inhibitors block the zinc metalloproteinase ZMPSTE24 and lead to an accumulation of prelamin A in cells"],"prefix":"10.1073","volume":"104","author":[{"given":"Catherine","family":"Coffinier","sequence":"first","affiliation":[{"name":"*Department of Medicine\/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah E.","family":"Hudon","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Purdue University, West Lafayette, IN 47907"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily A.","family":"Farber","sequence":"additional","affiliation":[{"name":"*Department of Medicine\/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandy Y.","family":"Chang","sequence":"additional","affiliation":[{"name":"*Department of Medicine\/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine A.","family":"Hrycyna","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Purdue University, West Lafayette, IN 47907"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen G.","family":"Young","sequence":"additional","affiliation":[{"name":"*Department of Medicine\/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loren G.","family":"Fong","sequence":"additional","affiliation":[{"name":"*Department of Medicine\/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2007,8,14]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199804303381808"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.med.58.072905.180040"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra041811"},{"key":"e_1_3_4_4_2","first-page":"383","volume":"25","author":"Vigouroux C","year":"1999","unstructured":"C Vigouroux, S Gharakhanian, Y Salhi, TH Nguy\u00ean, N Adda, W Rozenbaum, J Capeau Diabetes Metab 25, 383\u2013392 (1999).","journal-title":"Diabetes Metab"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1525-1497.2002.20201.x"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1097\/00002030-200304001-00017"},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1177\/135965350100600301","volume":"6","author":"Nolan D","year":"2001","unstructured":"D Nolan, M John, S Mallal Antivir Ther 6, 145\u2013160 (2001).","journal-title":"Antivir Ther"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1097\/00002030-200311210-00005"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1006\/mgme.2000.3092"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddg213"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.0022-202X.2005.23846.x"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi159"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R500011-JLR200"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.110.5.1489"},{"key":"e_1_3_4_15_2","first-page":"273","volume-title":"The Enzymes","author":"Young SG","year":"2005","unstructured":"SG Young, S Clarke, M Bergo, M Philips, LG Fong The Enzymes, eds S Clarke, F Tamanoi (Academic, San Diego, CA) Vol 24, 273\u2013301 (2005)."},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.192460799"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M102908200"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.275.5307.1796"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.136.2.271"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.2174\/138161207779313560"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2004.029751"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01629"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.13.8383"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C000831200"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(95)55023-2"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.9.6227"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M410292200"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.85.13.4643"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/cdg571"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0704212104","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,13]],"date-time":"2023-05-13T10:45:23Z","timestamp":1683974723000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0704212104"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,8,14]]},"references-count":29,"journal-issue":{"issue":"33","published-print":{"date-parts":[[2007,8,14]]}},"alternative-id":["10.1073\/pnas.0704212104"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0704212104","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.1090370.543619","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,8,14]]},"assertion":[{"value":"2007-05-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2007-08-14","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}