{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T02:47:27Z","timestamp":1791859647810,"version":"4.3.4"},"reference-count":32,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2013,12,30]],"date-time":"2013-12-30T00:00:00Z","timestamp":1388361600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2014,1]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>To investigate the role of autophagy in the regulation of cell death in rheumatoid arthritis synovial fibroblasts (RASFs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>RASFs and osteoarthritis synovial fibroblasts (OASFs) were treated with thapsigargin (TG), an inducer of endoplasmic reticulum (ER) stress, and MG132, a proteasome inhibitor. Then, 3\u2010methyladenine was used as an autophagy inhibitor and bafilomycin A1 as a lysosome inhibitor. Polyubiquitinated proteins, p62, and autophagy induction were evaluated by immunoblotting, immunofluorescence microscopy, and immunohistochemistry, respectively. OASFs were transfected with small interfering RNA targeting autophagy\u2010linked FYVE protein (ALFY). Cell death was evaluated by flow cytometry and a caspase 3 activity assay.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In RASFs, the induction of autophagy by TG and MG132 was increased compared to that in OASFs. Whereas autophagy promoted a caspase 3\u2013independent induction of cell death under ER stress, autophagy had a protective role in apoptosis induced by proteasome inhibition. Treatment of RASFs with 3\u2010methyladenine blocked TG\u2010induced cell death. ER stress induced a strong accumulation of p62\u2010positive polyubiquitinated protein aggregates, accompanied by the formation of large vacuoles in RASFs but not OASFs. Furthermore, TG\u2010induced p62 protein expression was increased, whereas TG\u2010induced ALFY expression was reduced, in RASFs compared to OASFs. ALFY knockdown promoted the accumulation of p62, the formation of polyubiquitinated protein aggregates, and cell death.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our data provide the first evidence of a dual role of autophagy in the regulation of death pathways in RASFs. A reduced expression of ALFY and the formation of p62\u2010positive polyubiquitinated protein aggregates promote cell death in RASFs under severe ER stress.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.38190","type":"journal-article","created":{"date-parts":[[2013,9,11]],"date-time":"2013-09-11T05:15:49Z","timestamp":1378876549000},"page":"40-48","source":"Crossref","is-referenced-by-count":139,"title":["Dual Role of Autophagy in Stress\u2010Induced Cell Death in Rheumatoid Arthritis Synovial Fibroblasts"],"prefix":"10.1002","volume":"66","author":[{"given":"Masaru","family":"Kato","sequence":"first","affiliation":[{"name":"Center of Experimental Rheumatology, University Hospital Zurich Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Ospelt","sequence":"additional","affiliation":[{"name":"Center of Experimental Rheumatology, University Hospital Zurich Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renate E.","family":"Gay","sequence":"additional","affiliation":[{"name":"Center of Experimental Rheumatology, University Hospital Zurich Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen","family":"Gay","sequence":"additional","affiliation":[{"name":"Center of Experimental Rheumatology, University Hospital Zurich Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin","family":"Klein","sequence":"additional","affiliation":[{"name":"Center of Experimental Rheumatology, University Hospital Zurich Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,12,30]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2010.07.004"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncprheum0699"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/446745a"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2010.09.023"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2011.96"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar2921"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780310302"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780290816"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.24140"},{"key":"e_1_2_7_11_1","first-page":"15.6","article-title":"Measurement of autophagic activity in mammalian cells","volume":"15","author":"Menzies FM","year":"2012","journal-title":"Curr Protoc Cell Biol"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.197491"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.01.028"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M802182200"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.10.035"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2009.04.026"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.01287"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.6.3.11226"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar3778"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20111783"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/17.8.1595"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4401359"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-03-2404"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2008.097709"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.27492"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.27690"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2012.08.003"},{"key":"e_1_2_7_28_1","first-page":"84","article-title":"An autophagy inhibitor enhances the inhibition of cell proliferation induced by a proteasome inhibitor in MCF\u20107 cells","volume":"5","author":"Yao F","year":"2012","journal-title":"Mol Med Rep"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.27586"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2990.2002.00394.x"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/62.12.1241"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2002.32674"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00011-012-0572-1"}],"container-title":["Arthritis &amp; 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