Ask1 gene deletion blocks maternal diabetes-induced endoplasmic reticulum stress in the developing embryo by disrupting the unfolded protein response signalosome
Apoptosis signal-regulating kinase 1 (ASK1) is activated by various stresses. The link between ASK1 activation and endoplasmic reticulum (ER) stress, two causal events in diabetic embryopathy, has not been determined. We sought to investigate whether ASK1 is involved in the unfolded protein response...
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| Veröffentlicht in: | Diabetes (New York, N.Y.) N.Y.), 2015-03, Vol.64 (3), p.973-988 |
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| creator | Wang, Fang Wu, Yanqing Gu, Hui Reece, E Albert Fang, Shengyun Gabbay-Benziv, Rinat Aberdeen, Graham Yang, Peixin |
| description | Apoptosis signal-regulating kinase 1 (ASK1) is activated by various stresses. The link between ASK1 activation and endoplasmic reticulum (ER) stress, two causal events in diabetic embryopathy, has not been determined. We sought to investigate whether ASK1 is involved in the unfolded protein response (UPR) that leads to ER stress. Deleting Ask1 abrogated diabetes-induced UPR by suppressing phosphorylation of inositol-requiring enzyme 1α (IRE1α), and double-stranded RNA-activated protein kinase (PKR)-like ER kinase (PERK) blocked the mitochondrial translocation of proapoptotic Bcl-2 members and ER stress. ASK1 participated in the IRE1α signalosome, and removing ASK1 abrogated the proapoptotic kinase activity of IRE1α. Ask1 deletion suppressed diabetes-induced IRE1α endoriboneclease activities, which led to X-box binding protein 1 mRNA cleavage, an ER stress marker, decreased expression of microRNAs, and increased expression of a miR-17 target, thioredoxin-interacting protein (Txnip), a thioredoxin binding protein, which enhanced ASK1 activation by disrupting the thioredoxin-ASK1 complexes. ASK1 is essential for the assembly and function of the IRE1α signalosome, which forms a positive feedback loop with ASK1 through Txnip. ASK1 knockdown in C17.2 neural stem cells diminished high glucose- or tunicamycin-induced IRE1α activation, which further supports our hypothesis that ASK1 plays a causal role in diabetes-induced ER stress and apoptosis. |
| doi_str_mv | 10.2337/db14-0409 |
| format | Article |
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The link between ASK1 activation and endoplasmic reticulum (ER) stress, two causal events in diabetic embryopathy, has not been determined. We sought to investigate whether ASK1 is involved in the unfolded protein response (UPR) that leads to ER stress. Deleting Ask1 abrogated diabetes-induced UPR by suppressing phosphorylation of inositol-requiring enzyme 1α (IRE1α), and double-stranded RNA-activated protein kinase (PKR)-like ER kinase (PERK) blocked the mitochondrial translocation of proapoptotic Bcl-2 members and ER stress. ASK1 participated in the IRE1α signalosome, and removing ASK1 abrogated the proapoptotic kinase activity of IRE1α. Ask1 deletion suppressed diabetes-induced IRE1α endoriboneclease activities, which led to X-box binding protein 1 mRNA cleavage, an ER stress marker, decreased expression of microRNAs, and increased expression of a miR-17 target, thioredoxin-interacting protein (Txnip), a thioredoxin binding protein, which enhanced ASK1 activation by disrupting the thioredoxin-ASK1 complexes. ASK1 is essential for the assembly and function of the IRE1α signalosome, which forms a positive feedback loop with ASK1 through Txnip. ASK1 knockdown in C17.2 neural stem cells diminished high glucose- or tunicamycin-induced IRE1α activation, which further supports our hypothesis that ASK1 plays a causal role in diabetes-induced ER stress and apoptosis.</description><identifier>ISSN: 0012-1797</identifier><identifier>EISSN: 1939-327X</identifier><identifier>DOI: 10.2337/db14-0409</identifier><identifier>PMID: 25249581</identifier><identifier>CODEN: DIAEAZ</identifier><language>eng</language><publisher>United States: American Diabetes Association</publisher><subject>Animals ; Apoptosis ; Carrier Proteins - genetics ; Carrier Proteins - metabolism ; Cells, Cultured ; Diabetes ; Diabetes, Gestational - genetics ; Diabetes, Gestational - metabolism ; Diabetes, Gestational - pathology ; Endoplasmic reticulum ; Endoplasmic Reticulum Stress - genetics ; Endoplasmic Reticulum Stress - physiology ; Endoribonucleases - genetics ; Endoribonucleases - metabolism ; Female ; Gene expression ; Immunoprecipitation ; In Situ Nick-End Labeling ; Kinases ; MAP Kinase Kinase Kinase 5 - deficiency ; MAP Kinase Kinase Kinase 5 - genetics ; MAP Kinase Kinase Kinase 5 - metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Pathophysiology ; Phosphorylation ; Pregnancy ; Protein-Serine-Threonine Kinases - genetics ; Protein-Serine-Threonine Kinases - metabolism ; Real-Time Polymerase Chain Reaction ; Stress response ; Thioredoxins - genetics ; Thioredoxins - metabolism ; Unfolded Protein Response - genetics ; Unfolded Protein Response - physiology</subject><ispartof>Diabetes (New York, N.Y.), 2015-03, Vol.64 (3), p.973-988</ispartof><rights>2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.</rights><rights>Copyright American Diabetes Association Mar 2015</rights><rights>2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c502t-505950a07fefdb88d70eca2fd15d8015d7c99c7b368f29e5073fd45de48ffc5f3</citedby><cites>FETCH-LOGICAL-c502t-505950a07fefdb88d70eca2fd15d8015d7c99c7b368f29e5073fd45de48ffc5f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338585/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338585/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25249581$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Fang</creatorcontrib><creatorcontrib>Wu, Yanqing</creatorcontrib><creatorcontrib>Gu, Hui</creatorcontrib><creatorcontrib>Reece, E Albert</creatorcontrib><creatorcontrib>Fang, Shengyun</creatorcontrib><creatorcontrib>Gabbay-Benziv, Rinat</creatorcontrib><creatorcontrib>Aberdeen, Graham</creatorcontrib><creatorcontrib>Yang, Peixin</creatorcontrib><title>Ask1 gene deletion blocks maternal diabetes-induced endoplasmic reticulum stress in the developing embryo by disrupting the unfolded protein response signalosome</title><title>Diabetes (New York, N.Y.)</title><addtitle>Diabetes</addtitle><description>Apoptosis signal-regulating kinase 1 (ASK1) is activated by various stresses. The link between ASK1 activation and endoplasmic reticulum (ER) stress, two causal events in diabetic embryopathy, has not been determined. We sought to investigate whether ASK1 is involved in the unfolded protein response (UPR) that leads to ER stress. Deleting Ask1 abrogated diabetes-induced UPR by suppressing phosphorylation of inositol-requiring enzyme 1α (IRE1α), and double-stranded RNA-activated protein kinase (PKR)-like ER kinase (PERK) blocked the mitochondrial translocation of proapoptotic Bcl-2 members and ER stress. ASK1 participated in the IRE1α signalosome, and removing ASK1 abrogated the proapoptotic kinase activity of IRE1α. Ask1 deletion suppressed diabetes-induced IRE1α endoriboneclease activities, which led to X-box binding protein 1 mRNA cleavage, an ER stress marker, decreased expression of microRNAs, and increased expression of a miR-17 target, thioredoxin-interacting protein (Txnip), a thioredoxin binding protein, which enhanced ASK1 activation by disrupting the thioredoxin-ASK1 complexes. ASK1 is essential for the assembly and function of the IRE1α signalosome, which forms a positive feedback loop with ASK1 through Txnip. ASK1 knockdown in C17.2 neural stem cells diminished high glucose- or tunicamycin-induced IRE1α activation, which further supports our hypothesis that ASK1 plays a causal role in diabetes-induced ER stress and apoptosis.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Carrier Proteins - genetics</subject><subject>Carrier Proteins - metabolism</subject><subject>Cells, Cultured</subject><subject>Diabetes</subject><subject>Diabetes, Gestational - genetics</subject><subject>Diabetes, Gestational - metabolism</subject><subject>Diabetes, Gestational - pathology</subject><subject>Endoplasmic reticulum</subject><subject>Endoplasmic Reticulum Stress - genetics</subject><subject>Endoplasmic Reticulum Stress - physiology</subject><subject>Endoribonucleases - genetics</subject><subject>Endoribonucleases - metabolism</subject><subject>Female</subject><subject>Gene expression</subject><subject>Immunoprecipitation</subject><subject>In Situ Nick-End Labeling</subject><subject>Kinases</subject><subject>MAP Kinase Kinase Kinase 5 - deficiency</subject><subject>MAP Kinase Kinase Kinase 5 - genetics</subject><subject>MAP Kinase Kinase Kinase 5 - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Pathophysiology</subject><subject>Phosphorylation</subject><subject>Pregnancy</subject><subject>Protein-Serine-Threonine Kinases - genetics</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Stress response</subject><subject>Thioredoxins - genetics</subject><subject>Thioredoxins - metabolism</subject><subject>Unfolded Protein Response - genetics</subject><subject>Unfolded Protein Response - physiology</subject><issn>0012-1797</issn><issn>1939-327X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkl2LFSEYx4co2tPWRV8ghG7qYsqX8ag3wbL0BgvdFHQ3OPp41l1HJ3UWzsfpm-aw21LdhKCgv-en8vy77jnBbyhj4q2dyNDjAasH3Y4opnpGxfeH3Q5jQnsilDjpnpRyhTHet_G4O6GcDopLsut-npVrgg4QAVkIUH2KaArJXBc06wo56oCs1xNUKL2PdjVgEUSblqDL7A3KrcasYZ1RqRlKQT6iernZbiCkxccDgnnKx4SmYzOVvC5129yYNboUbBMuOVVohU2wpFgAFX9oN6eSZnjaPXI6FHh2t5523z68_3r-qb_48vHz-dlFbzimteeYK441Fg6cnaS0AoPR1FnCrcRtEkYpIya2l44q4FgwZwduYZDOGe7Yaffu1rus0wzWQKxZh3HJftb5OCbtx79Por8cD-lmHBiTXPImeHUnyOnHCqWOsy8GQtAR0lpGIglRWLWe_B_dcynwMCjW0Jf_oFdp3dqyUXtMGKV0aNTrW8rkVEoGd_9ugsctI-OWkXHLSGNf_PnRe_J3KNgvaAi8IQ</recordid><startdate>20150301</startdate><enddate>20150301</enddate><creator>Wang, Fang</creator><creator>Wu, Yanqing</creator><creator>Gu, Hui</creator><creator>Reece, E Albert</creator><creator>Fang, Shengyun</creator><creator>Gabbay-Benziv, Rinat</creator><creator>Aberdeen, Graham</creator><creator>Yang, Peixin</creator><general>American Diabetes Association</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20150301</creationdate><title>Ask1 gene deletion blocks maternal diabetes-induced endoplasmic reticulum stress in the developing embryo by disrupting the unfolded protein response signalosome</title><author>Wang, Fang ; Wu, Yanqing ; Gu, Hui ; Reece, E Albert ; Fang, Shengyun ; Gabbay-Benziv, Rinat ; Aberdeen, Graham ; Yang, Peixin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c502t-505950a07fefdb88d70eca2fd15d8015d7c99c7b368f29e5073fd45de48ffc5f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>Carrier Proteins - genetics</topic><topic>Carrier Proteins - metabolism</topic><topic>Cells, Cultured</topic><topic>Diabetes</topic><topic>Diabetes, Gestational - genetics</topic><topic>Diabetes, Gestational - metabolism</topic><topic>Diabetes, Gestational - pathology</topic><topic>Endoplasmic reticulum</topic><topic>Endoplasmic Reticulum Stress - genetics</topic><topic>Endoplasmic Reticulum Stress - physiology</topic><topic>Endoribonucleases - genetics</topic><topic>Endoribonucleases - metabolism</topic><topic>Female</topic><topic>Gene expression</topic><topic>Immunoprecipitation</topic><topic>In Situ Nick-End Labeling</topic><topic>Kinases</topic><topic>MAP Kinase Kinase Kinase 5 - deficiency</topic><topic>MAP Kinase Kinase Kinase 5 - genetics</topic><topic>MAP Kinase Kinase Kinase 5 - metabolism</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Pathophysiology</topic><topic>Phosphorylation</topic><topic>Pregnancy</topic><topic>Protein-Serine-Threonine Kinases - genetics</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Real-Time Polymerase Chain Reaction</topic><topic>Stress response</topic><topic>Thioredoxins - genetics</topic><topic>Thioredoxins - metabolism</topic><topic>Unfolded Protein Response - genetics</topic><topic>Unfolded Protein Response - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Fang</creatorcontrib><creatorcontrib>Wu, Yanqing</creatorcontrib><creatorcontrib>Gu, Hui</creatorcontrib><creatorcontrib>Reece, E Albert</creatorcontrib><creatorcontrib>Fang, Shengyun</creatorcontrib><creatorcontrib>Gabbay-Benziv, Rinat</creatorcontrib><creatorcontrib>Aberdeen, Graham</creatorcontrib><creatorcontrib>Yang, Peixin</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Diabetes (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Fang</au><au>Wu, Yanqing</au><au>Gu, Hui</au><au>Reece, E Albert</au><au>Fang, Shengyun</au><au>Gabbay-Benziv, Rinat</au><au>Aberdeen, Graham</au><au>Yang, Peixin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ask1 gene deletion blocks maternal diabetes-induced endoplasmic reticulum stress in the developing embryo by disrupting the unfolded protein response signalosome</atitle><jtitle>Diabetes (New York, N.Y.)</jtitle><addtitle>Diabetes</addtitle><date>2015-03-01</date><risdate>2015</risdate><volume>64</volume><issue>3</issue><spage>973</spage><epage>988</epage><pages>973-988</pages><issn>0012-1797</issn><eissn>1939-327X</eissn><coden>DIAEAZ</coden><abstract>Apoptosis signal-regulating kinase 1 (ASK1) is activated by various stresses. The link between ASK1 activation and endoplasmic reticulum (ER) stress, two causal events in diabetic embryopathy, has not been determined. We sought to investigate whether ASK1 is involved in the unfolded protein response (UPR) that leads to ER stress. Deleting Ask1 abrogated diabetes-induced UPR by suppressing phosphorylation of inositol-requiring enzyme 1α (IRE1α), and double-stranded RNA-activated protein kinase (PKR)-like ER kinase (PERK) blocked the mitochondrial translocation of proapoptotic Bcl-2 members and ER stress. ASK1 participated in the IRE1α signalosome, and removing ASK1 abrogated the proapoptotic kinase activity of IRE1α. Ask1 deletion suppressed diabetes-induced IRE1α endoriboneclease activities, which led to X-box binding protein 1 mRNA cleavage, an ER stress marker, decreased expression of microRNAs, and increased expression of a miR-17 target, thioredoxin-interacting protein (Txnip), a thioredoxin binding protein, which enhanced ASK1 activation by disrupting the thioredoxin-ASK1 complexes. ASK1 is essential for the assembly and function of the IRE1α signalosome, which forms a positive feedback loop with ASK1 through Txnip. ASK1 knockdown in C17.2 neural stem cells diminished high glucose- or tunicamycin-induced IRE1α activation, which further supports our hypothesis that ASK1 plays a causal role in diabetes-induced ER stress and apoptosis.</abstract><cop>United States</cop><pub>American Diabetes Association</pub><pmid>25249581</pmid><doi>10.2337/db14-0409</doi><tpages>16</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Apoptosis Carrier Proteins - genetics Carrier Proteins - metabolism Cells, Cultured Diabetes Diabetes, Gestational - genetics Diabetes, Gestational - metabolism Diabetes, Gestational - pathology Endoplasmic reticulum Endoplasmic Reticulum Stress - genetics Endoplasmic Reticulum Stress - physiology Endoribonucleases - genetics Endoribonucleases - metabolism Female Gene expression Immunoprecipitation In Situ Nick-End Labeling Kinases MAP Kinase Kinase Kinase 5 - deficiency MAP Kinase Kinase Kinase 5 - genetics MAP Kinase Kinase Kinase 5 - metabolism Mice Mice, Inbred C57BL Mice, Knockout Pathophysiology Phosphorylation Pregnancy Protein-Serine-Threonine Kinases - genetics Protein-Serine-Threonine Kinases - metabolism Real-Time Polymerase Chain Reaction Stress response Thioredoxins - genetics Thioredoxins - metabolism Unfolded Protein Response - genetics Unfolded Protein Response - physiology |
| title | Ask1 gene deletion blocks maternal diabetes-induced endoplasmic reticulum stress in the developing embryo by disrupting the unfolded protein response signalosome |
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