Linked Life Data

19838173

Source:http://linkedlifedata.com/resource/pubmed/id/19838173

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
11
pubmed:dateCreated
2009-11-3
pubmed:abstractText
Autophagy is an active homeostatic degradation process for the removal or turnover of cytoplasmic components wherein the LC3 ubiquitin-like protein undergoes an Atg7 E1-like enzyme/Atg3 E2-like enzyme-mediated conjugation process to induce autophagosome biogenesis. Besides its cytoprotective role, autophagy acts on cell death when it is abnormally upregulated. Thus, the autophagy pathway requires tight regulation to ensure that this degradative process is well balanced. Two death effector domains (DED1/2) containing cellular FLICE-like inhibitor protein (cFLIP) and viral FLIP (vFLIP) of Kaposi's sarcoma-associated herpesvirus (KSHV), Herpesvirus saimiri (HVS), and Molluscum contagiosum virus (MCV) protect cells from apoptosis mediated by death receptors. Here, we report that cellular and viral FLIPs suppress autophagy by preventing Atg3 from binding and processing LC3. Consequently, FLIP expression effectively represses cell death with autophagy, as induced by rapamycin, an mTor inhibitor and an effective anti-tumour drug against KSHV-induced Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). Remarkably, either a DED1 alpha2-helix ten amino-acid (alpha2) peptide or a DED2 alpha4-helix twelve amino-acid (alpha4) peptide of FLIP is individually sufficient for binding FLIP itself and Atg3, with the peptide interactions effectively suppressing Atg3-FLIP interaction without affecting Atg3-LC3 interaction, resulting in robust cell death with autophagy. Our study thus identifies a checkpoint of the autophagy pathway where cellular and viral FLIPs limit the Atg3-mediated step of LC3 conjugation to regulate autophagosome biogenesis. Furthermore, the FLIP-derived short peptides induce growth suppression and cell death with autophagy, representing biologically active molecules for potential anti-cancer therapies.
pubmed:grant
http://linkedlifedata.com/resource/pubmed/grant/AI073099, http://linkedlifedata.com/resource/pubmed/grant/AI083841, http://linkedlifedata.com/resource/pubmed/grant/CA115284, http://linkedlifedata.com/resource/pubmed/grant/CA140964, http://linkedlifedata.com/resource/pubmed/grant/CA31363, http://linkedlifedata.com/resource/pubmed/grant/CA82057, http://linkedlifedata.com/resource/pubmed/grant/CA91819, http://linkedlifedata.com/resource/pubmed/grant/R01 CA096512-05, http://linkedlifedata.com/resource/pubmed/grant/R01 CA096512-06, http://linkedlifedata.com/resource/pubmed/grant/R01 CA124332-02, http://linkedlifedata.com/resource/pubmed/grant/R01 CA124332-03, http://linkedlifedata.com/resource/pubmed/grant/R01 CA124332-05, http://linkedlifedata.com/resource/pubmed/grant/R01 CA132637-01A1, http://linkedlifedata.com/resource/pubmed/grant/R01 CA132637-02, http://linkedlifedata.com/resource/pubmed/grant/R01 CA132637-04, http://linkedlifedata.com/resource/pubmed/grant/RR00168
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
1476-4679
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
11
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1355-62
pubmed:dateRevised
2010-12-17
pubmed:meshHeading
pubmed:year
2009
pubmed:articleTitle
FLIP-mediated autophagy regulation in cell death control.
pubmed:affiliation
Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Harlyne J. Norris Cancer Research Tower, 1450 Biggy Street, Los Angeles, California 90033, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural