Nutrient-deprivation autophagy factor-1 (NAF-1): biochemical properties of a novel cellular target for anti-diabetic drugs
Nutrient-deprivation autophagy factor-1 (NAF-1) (synonyms: Cisd2, Eris, Miner1, and Noxp70) is a [2Fe-2S] cluster protein immune-detected both in endoplasmic reticulum (ER) and mitochondrial outer membrane. It was implicated in human pathology (Wolfram Syndrome 2) and in BCL-2 mediated antagonizatio...
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| creator | Tamir, Sagi Zuris, John A Agranat, Lily Lipper, Colin H Conlan, Andrea R Michaeli, Dorit Harir, Yael Paddock, Mark L Mittler, Ron Cabantchik, Zvi Ioav Jennings, Patricia A Nechushtai, Rachel |
| description | Nutrient-deprivation autophagy factor-1 (NAF-1) (synonyms: Cisd2, Eris, Miner1, and Noxp70) is a [2Fe-2S] cluster protein immune-detected both in endoplasmic reticulum (ER) and mitochondrial outer membrane. It was implicated in human pathology (Wolfram Syndrome 2) and in BCL-2 mediated antagonization of Beclin 1-dependent autophagy and depression of ER calcium stores. To gain insights about NAF-1 functions, we investigated the biochemical properties of its 2Fe-2S cluster and sensitivity of those properties to small molecules. The structure of the soluble domain of NAF-1 shows that it forms a homodimer with each protomer containing a [2Fe-2S] cluster bound by 3 Cys and one His. NAF-1 has shown the unusual abilities to transfer its 2Fe-2S cluster to an apo-acceptor protein (followed in vitro by spectrophotometry and by native PAGE electrophoresis) and to transfer iron to intact mitochondria in cell models (monitored by fluorescence imaging with iron fluorescent sensors targeted to mitochondria). Importantly, the drug pioglitazone abrogates NAF-1's ability to transfer the cluster to acceptor proteins and iron to mitochondria. Similar effects were found for the anti-diabetes and longevity-promoting antioxidant resveratrol. These results reveal NAF-1 as a previously unidentified cell target of anti-diabetes thiazolidinedione drugs like pioglitazone and of the natural product resveratrol, both of which interact with the protein and stabilize its labile [2Fe-2S] cluster. |
| doi_str_mv | 10.1371/journal.pone.0061202 |
| format | Article |
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It was implicated in human pathology (Wolfram Syndrome 2) and in BCL-2 mediated antagonization of Beclin 1-dependent autophagy and depression of ER calcium stores. To gain insights about NAF-1 functions, we investigated the biochemical properties of its 2Fe-2S cluster and sensitivity of those properties to small molecules. The structure of the soluble domain of NAF-1 shows that it forms a homodimer with each protomer containing a [2Fe-2S] cluster bound by 3 Cys and one His. NAF-1 has shown the unusual abilities to transfer its 2Fe-2S cluster to an apo-acceptor protein (followed in vitro by spectrophotometry and by native PAGE electrophoresis) and to transfer iron to intact mitochondria in cell models (monitored by fluorescence imaging with iron fluorescent sensors targeted to mitochondria). Importantly, the drug pioglitazone abrogates NAF-1's ability to transfer the cluster to acceptor proteins and iron to mitochondria. Similar effects were found for the anti-diabetes and longevity-promoting antioxidant resveratrol. These results reveal NAF-1 as a previously unidentified cell target of anti-diabetes thiazolidinedione drugs like pioglitazone and of the natural product resveratrol, both of which interact with the protein and stabilize its labile [2Fe-2S] cluster.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0061202</identifier><identifier>PMID: 23717386</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Antidiabetics ; Antioxidants ; Autophagy ; Bcl-2 protein ; Biochemistry ; Biology ; Calcium ; Cell culture ; Cell death ; Cells, Cultured ; Chemistry ; Clusters ; Deprivation ; Diabetes ; Diabetes mellitus ; Drug Delivery Systems - methods ; Drugs ; Endoplasmic reticulum ; Eris (dwarf planet) ; Fluorescence ; Fluorides ; Human pathology ; Humans ; Hypoglycemic agents ; Hypoglycemic Agents - metabolism ; Hypoglycemic Agents - pharmacology ; Immunosuppressive agents ; Iron ; Iron - metabolism ; Kinases ; Life sciences ; Ligands ; Mental depression ; Mitochondria ; Mitochondria - drug effects ; Mitochondria - metabolism ; Molecular structure ; Nutrients ; Oxidation-Reduction - drug effects ; Oxidative stress ; Phagocytosis ; Physics ; Pioglitazone ; Properties (attributes) ; Protein Subunits - metabolism ; Proteins ; Resveratrol ; Ribonucleoproteins - metabolism ; Small Molecule Libraries - metabolism ; Small Molecule Libraries - therapeutic use ; Spectrophotometry ; Sulfur ; Thiazolidinediones - metabolism ; Thiazolidinediones - pharmacology</subject><ispartof>PloS one, 2013-05, Vol.8 (5), p.e61202-e61202</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Tamir et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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It was implicated in human pathology (Wolfram Syndrome 2) and in BCL-2 mediated antagonization of Beclin 1-dependent autophagy and depression of ER calcium stores. To gain insights about NAF-1 functions, we investigated the biochemical properties of its 2Fe-2S cluster and sensitivity of those properties to small molecules. The structure of the soluble domain of NAF-1 shows that it forms a homodimer with each protomer containing a [2Fe-2S] cluster bound by 3 Cys and one His. NAF-1 has shown the unusual abilities to transfer its 2Fe-2S cluster to an apo-acceptor protein (followed in vitro by spectrophotometry and by native PAGE electrophoresis) and to transfer iron to intact mitochondria in cell models (monitored by fluorescence imaging with iron fluorescent sensors targeted to mitochondria). Importantly, the drug pioglitazone abrogates NAF-1's ability to transfer the cluster to acceptor proteins and iron to mitochondria. Similar effects were found for the anti-diabetes and longevity-promoting antioxidant resveratrol. These results reveal NAF-1 as a previously unidentified cell target of anti-diabetes thiazolidinedione drugs like pioglitazone and of the natural product resveratrol, both of which interact with the protein and stabilize its labile [2Fe-2S] cluster.</description><subject>Antidiabetics</subject><subject>Antioxidants</subject><subject>Autophagy</subject><subject>Bcl-2 protein</subject><subject>Biochemistry</subject><subject>Biology</subject><subject>Calcium</subject><subject>Cell culture</subject><subject>Cell death</subject><subject>Cells, Cultured</subject><subject>Chemistry</subject><subject>Clusters</subject><subject>Deprivation</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Drug Delivery Systems - methods</subject><subject>Drugs</subject><subject>Endoplasmic reticulum</subject><subject>Eris (dwarf planet)</subject><subject>Fluorescence</subject><subject>Fluorides</subject><subject>Human pathology</subject><subject>Humans</subject><subject>Hypoglycemic agents</subject><subject>Hypoglycemic Agents - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tamir, Sagi</au><au>Zuris, John A</au><au>Agranat, Lily</au><au>Lipper, Colin H</au><au>Conlan, Andrea R</au><au>Michaeli, Dorit</au><au>Harir, Yael</au><au>Paddock, Mark L</au><au>Mittler, Ron</au><au>Cabantchik, Zvi Ioav</au><au>Jennings, Patricia A</au><au>Nechushtai, Rachel</au><au>Levy, Yaakov Koby</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nutrient-deprivation autophagy factor-1 (NAF-1): biochemical properties of a novel cellular target for anti-diabetic drugs</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-05-22</date><risdate>2013</risdate><volume>8</volume><issue>5</issue><spage>e61202</spage><epage>e61202</epage><pages>e61202-e61202</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Nutrient-deprivation autophagy factor-1 (NAF-1) (synonyms: Cisd2, Eris, Miner1, and Noxp70) is a [2Fe-2S] cluster protein immune-detected both in endoplasmic reticulum (ER) and mitochondrial outer membrane. It was implicated in human pathology (Wolfram Syndrome 2) and in BCL-2 mediated antagonization of Beclin 1-dependent autophagy and depression of ER calcium stores. To gain insights about NAF-1 functions, we investigated the biochemical properties of its 2Fe-2S cluster and sensitivity of those properties to small molecules. The structure of the soluble domain of NAF-1 shows that it forms a homodimer with each protomer containing a [2Fe-2S] cluster bound by 3 Cys and one His. NAF-1 has shown the unusual abilities to transfer its 2Fe-2S cluster to an apo-acceptor protein (followed in vitro by spectrophotometry and by native PAGE electrophoresis) and to transfer iron to intact mitochondria in cell models (monitored by fluorescence imaging with iron fluorescent sensors targeted to mitochondria). Importantly, the drug pioglitazone abrogates NAF-1's ability to transfer the cluster to acceptor proteins and iron to mitochondria. Similar effects were found for the anti-diabetes and longevity-promoting antioxidant resveratrol. These results reveal NAF-1 as a previously unidentified cell target of anti-diabetes thiazolidinedione drugs like pioglitazone and of the natural product resveratrol, both of which interact with the protein and stabilize its labile [2Fe-2S] cluster.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23717386</pmid><doi>10.1371/journal.pone.0061202</doi><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1354337075 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Antidiabetics Antioxidants Autophagy Bcl-2 protein Biochemistry Biology Calcium Cell culture Cell death Cells, Cultured Chemistry Clusters Deprivation Diabetes Diabetes mellitus Drug Delivery Systems - methods Drugs Endoplasmic reticulum Eris (dwarf planet) Fluorescence Fluorides Human pathology Humans Hypoglycemic agents Hypoglycemic Agents - metabolism Hypoglycemic Agents - pharmacology Immunosuppressive agents Iron Iron - metabolism Kinases Life sciences Ligands Mental depression Mitochondria Mitochondria - drug effects Mitochondria - metabolism Molecular structure Nutrients Oxidation-Reduction - drug effects Oxidative stress Phagocytosis Physics Pioglitazone Properties (attributes) Protein Subunits - metabolism Proteins Resveratrol Ribonucleoproteins - metabolism Small Molecule Libraries - metabolism Small Molecule Libraries - therapeutic use Spectrophotometry Sulfur Thiazolidinediones - metabolism Thiazolidinediones - pharmacology |
| title | Nutrient-deprivation autophagy factor-1 (NAF-1): biochemical properties of a novel cellular target for anti-diabetic drugs |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-31T00%3A05%3A49IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Nutrient-deprivation%20autophagy%20factor-1%20(NAF-1):%20biochemical%20properties%20of%20a%20novel%20cellular%20target%20for%20anti-diabetic%20drugs&rft.jtitle=PloS%20one&rft.au=Tamir,%20Sagi&rft.date=2013-05-22&rft.volume=8&rft.issue=5&rft.spage=e61202&rft.epage=e61202&rft.pages=e61202-e61202&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0061202&rft_dat=%3Cgale_plos_%3EA478165428%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1354337075&rft_id=info:pmid/23717386&rft_galeid=A478165428&rft_doaj_id=oai_doaj_org_article_784e2a071f1348ef8f98f442fc369770&rfr_iscdi=true |