Deletion of Autophagy-related 5 (Atg5) and Pik3c3 Genes in the Lens Causes Cataract Independent of Programmed Organelle Degradation
The lens of the eye is composed of fiber cells, which differentiate from epithelial cells and undergo programmed organelle degradation during terminal differentiation. Although autophagy, a major intracellular degradation system, is constitutively active in these cells, its physiological role has re...
Gespeichert in:
Veröffentlicht in: | The Journal of biological chemistry 2013-04, Vol.288 (16), p.11436-11447 |
---|---|
Hauptverfasser: | , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | 11447 |
---|---|
container_issue | 16 |
container_start_page | 11436 |
container_title | The Journal of biological chemistry |
container_volume | 288 |
creator | Morishita, Hideaki Eguchi, Satoshi Kimura, Hirotaka Sasaki, Junko Sakamaki, Yuriko Robinson, Michael L. Sasaki, Takehiko Mizushima, Noboru |
description | The lens of the eye is composed of fiber cells, which differentiate from epithelial cells and undergo programmed organelle degradation during terminal differentiation. Although autophagy, a major intracellular degradation system, is constitutively active in these cells, its physiological role has remained unclear. We have previously shown that Atg5-dependent macroautophagy is not necessary for lens organelle degradation, at least during the embryonic period. Here, we generated lens-specific Atg5 knock-out mice and showed that Atg5 is not required for lens organelle degradation at any period of life. However, deletion of Atg5 in the lens results in age-related cataract, which is accompanied by accumulation of polyubiquitinated and oxidized proteins, p62, and insoluble crystallins, suggesting a defect in intracellular quality control. We also produced lens-specific Pik3c3 knock-out mice to elucidate the possible involvement of Atg5-independent alternative autophagy, which is proposed to be dependent on Pik3c3 (also known as Vps34), in lens organelle degradation. Deletion of Pik3c3 in the lens does not affect lens organelle degradation, but it leads to congenital cataract and a defect in lens development after birth likely due to an impairment of the endocytic pathway. Taken together, these results suggest that clearance of lens organelles is independent of macroautophagy. These findings also clarify the physiological role of Atg5 and Pik3c3 in quality control and development of the lens, respectively.
Background: The role of autophagy-dependent quality control in the lens remains unclear.
Results: Deletion of Atg5 and Pik3c3/Vps34 in the lens does not affect programmed organelle degradation but causes cataract and a developmental defect, respectively.
Conclusion: These genes are important for quality control and development of the lens.
Significance: This study provides new insights into biology and age-related pathology of the lens. |
doi_str_mv | 10.1074/jbc.M112.437103 |
format | Article |
fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3630873</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0021925820672192</els_id><sourcerecordid>1338393872</sourcerecordid><originalsourceid>FETCH-LOGICAL-c509t-49d3fa10175d37af2c91b87ef2933dc47e7e93345730efd78c0e9e374c0e0c123</originalsourceid><addsrcrecordid>eNp1UUFvFCEYJUZj1-rZm-HYHmYL883IcDHZbLU2WdMeNPFGWPhmljoLKzBNevaPy2Rrowc58Ai8773v4xHylrMlZ6K5uNua5RfO62UDgjN4RhacdVBBy78_JwvGal7Juu1OyKuU7lhZjeQvyUkNjZAC6gX5dYkjZhc8DT1dTTkcdnp4qCKOOqOlLT1b5aE9p9pbeut-gAF6hR4TdZ7mHdIN-kTXeko4Q9ZRm0yvvcUDls3nWfY2hiHq_b7o3cRBexxHpJdY7qyerV-TF70eE755xFPy7dPHr-vP1ebm6nq92lSmZTJXjbTQa864aC0I3ddG8m0nsK8lgDWNQIHl1LQCGPZWdIahRBBNQWZ4Dafkw1H3MG1LM6a0F_WoDtHtdXxQQTv174t3OzWEewXvgXUCisDZo0AMPydMWe1dMmWcMlOYkuIAHUjoxOx1caSaGFKK2D_ZcKbm6FSJTs3RqWN0peLd39098f9kVQjySMDyR_cOo0rGoTdoXUSTlQ3uv-K_AXBnqOo</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1338393872</pqid></control><display><type>article</type><title>Deletion of Autophagy-related 5 (Atg5) and Pik3c3 Genes in the Lens Causes Cataract Independent of Programmed Organelle Degradation</title><source>MEDLINE</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><creator>Morishita, Hideaki ; Eguchi, Satoshi ; Kimura, Hirotaka ; Sasaki, Junko ; Sakamaki, Yuriko ; Robinson, Michael L. ; Sasaki, Takehiko ; Mizushima, Noboru</creator><creatorcontrib>Morishita, Hideaki ; Eguchi, Satoshi ; Kimura, Hirotaka ; Sasaki, Junko ; Sakamaki, Yuriko ; Robinson, Michael L. ; Sasaki, Takehiko ; Mizushima, Noboru</creatorcontrib><description>The lens of the eye is composed of fiber cells, which differentiate from epithelial cells and undergo programmed organelle degradation during terminal differentiation. Although autophagy, a major intracellular degradation system, is constitutively active in these cells, its physiological role has remained unclear. We have previously shown that Atg5-dependent macroautophagy is not necessary for lens organelle degradation, at least during the embryonic period. Here, we generated lens-specific Atg5 knock-out mice and showed that Atg5 is not required for lens organelle degradation at any period of life. However, deletion of Atg5 in the lens results in age-related cataract, which is accompanied by accumulation of polyubiquitinated and oxidized proteins, p62, and insoluble crystallins, suggesting a defect in intracellular quality control. We also produced lens-specific Pik3c3 knock-out mice to elucidate the possible involvement of Atg5-independent alternative autophagy, which is proposed to be dependent on Pik3c3 (also known as Vps34), in lens organelle degradation. Deletion of Pik3c3 in the lens does not affect lens organelle degradation, but it leads to congenital cataract and a defect in lens development after birth likely due to an impairment of the endocytic pathway. Taken together, these results suggest that clearance of lens organelles is independent of macroautophagy. These findings also clarify the physiological role of Atg5 and Pik3c3 in quality control and development of the lens, respectively.
Background: The role of autophagy-dependent quality control in the lens remains unclear.
Results: Deletion of Atg5 and Pik3c3/Vps34 in the lens does not affect programmed organelle degradation but causes cataract and a developmental defect, respectively.
Conclusion: These genes are important for quality control and development of the lens.
Significance: This study provides new insights into biology and age-related pathology of the lens.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M112.437103</identifier><identifier>PMID: 23479732</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Autophagy ; Autophagy - genetics ; Autophagy-Related Protein 5 ; Cataract ; Cataract - embryology ; Cataract - genetics ; Cataract - pathology ; Cell Biology ; Class III Phosphatidylinositol 3-Kinases - genetics ; Class III Phosphatidylinositol 3-Kinases - metabolism ; Crystallins - genetics ; Crystallins - metabolism ; Endocytosis - genetics ; Lens ; Lens Capsule, Crystalline - embryology ; Lens Capsule, Crystalline - pathology ; Mice ; Mice, Knockout ; Microtubule-Associated Proteins - genetics ; Microtubule-Associated Proteins - metabolism ; Organelle Degradation ; Organelles - genetics ; Organelles - metabolism ; Organelles - pathology ; Protein Degradation ; Quality Control ; Ubiquitin ; Ubiquitinated Proteins - genetics ; Ubiquitinated Proteins - metabolism</subject><ispartof>The Journal of biological chemistry, 2013-04, Vol.288 (16), p.11436-11447</ispartof><rights>2013 © 2013 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><rights>2013 by The American Society for Biochemistry and Molecular Biology, Inc. 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c509t-49d3fa10175d37af2c91b87ef2933dc47e7e93345730efd78c0e9e374c0e0c123</citedby><cites>FETCH-LOGICAL-c509t-49d3fa10175d37af2c91b87ef2933dc47e7e93345730efd78c0e9e374c0e0c123</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/PMC3630873/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3630873/$$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/23479732$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Morishita, Hideaki</creatorcontrib><creatorcontrib>Eguchi, Satoshi</creatorcontrib><creatorcontrib>Kimura, Hirotaka</creatorcontrib><creatorcontrib>Sasaki, Junko</creatorcontrib><creatorcontrib>Sakamaki, Yuriko</creatorcontrib><creatorcontrib>Robinson, Michael L.</creatorcontrib><creatorcontrib>Sasaki, Takehiko</creatorcontrib><creatorcontrib>Mizushima, Noboru</creatorcontrib><title>Deletion of Autophagy-related 5 (Atg5) and Pik3c3 Genes in the Lens Causes Cataract Independent of Programmed Organelle Degradation</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>The lens of the eye is composed of fiber cells, which differentiate from epithelial cells and undergo programmed organelle degradation during terminal differentiation. Although autophagy, a major intracellular degradation system, is constitutively active in these cells, its physiological role has remained unclear. We have previously shown that Atg5-dependent macroautophagy is not necessary for lens organelle degradation, at least during the embryonic period. Here, we generated lens-specific Atg5 knock-out mice and showed that Atg5 is not required for lens organelle degradation at any period of life. However, deletion of Atg5 in the lens results in age-related cataract, which is accompanied by accumulation of polyubiquitinated and oxidized proteins, p62, and insoluble crystallins, suggesting a defect in intracellular quality control. We also produced lens-specific Pik3c3 knock-out mice to elucidate the possible involvement of Atg5-independent alternative autophagy, which is proposed to be dependent on Pik3c3 (also known as Vps34), in lens organelle degradation. Deletion of Pik3c3 in the lens does not affect lens organelle degradation, but it leads to congenital cataract and a defect in lens development after birth likely due to an impairment of the endocytic pathway. Taken together, these results suggest that clearance of lens organelles is independent of macroautophagy. These findings also clarify the physiological role of Atg5 and Pik3c3 in quality control and development of the lens, respectively.
Background: The role of autophagy-dependent quality control in the lens remains unclear.
Results: Deletion of Atg5 and Pik3c3/Vps34 in the lens does not affect programmed organelle degradation but causes cataract and a developmental defect, respectively.
Conclusion: These genes are important for quality control and development of the lens.
Significance: This study provides new insights into biology and age-related pathology of the lens.</description><subject>Animals</subject><subject>Autophagy</subject><subject>Autophagy - genetics</subject><subject>Autophagy-Related Protein 5</subject><subject>Cataract</subject><subject>Cataract - embryology</subject><subject>Cataract - genetics</subject><subject>Cataract - pathology</subject><subject>Cell Biology</subject><subject>Class III Phosphatidylinositol 3-Kinases - genetics</subject><subject>Class III Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Crystallins - genetics</subject><subject>Crystallins - metabolism</subject><subject>Endocytosis - genetics</subject><subject>Lens</subject><subject>Lens Capsule, Crystalline - embryology</subject><subject>Lens Capsule, Crystalline - pathology</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Microtubule-Associated Proteins - genetics</subject><subject>Microtubule-Associated Proteins - metabolism</subject><subject>Organelle Degradation</subject><subject>Organelles - genetics</subject><subject>Organelles - metabolism</subject><subject>Organelles - pathology</subject><subject>Protein Degradation</subject><subject>Quality Control</subject><subject>Ubiquitin</subject><subject>Ubiquitinated Proteins - genetics</subject><subject>Ubiquitinated Proteins - metabolism</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1UUFvFCEYJUZj1-rZm-HYHmYL883IcDHZbLU2WdMeNPFGWPhmljoLKzBNevaPy2Rrowc58Ai8773v4xHylrMlZ6K5uNua5RfO62UDgjN4RhacdVBBy78_JwvGal7Juu1OyKuU7lhZjeQvyUkNjZAC6gX5dYkjZhc8DT1dTTkcdnp4qCKOOqOlLT1b5aE9p9pbeut-gAF6hR4TdZ7mHdIN-kTXeko4Q9ZRm0yvvcUDls3nWfY2hiHq_b7o3cRBexxHpJdY7qyerV-TF70eE755xFPy7dPHr-vP1ebm6nq92lSmZTJXjbTQa864aC0I3ddG8m0nsK8lgDWNQIHl1LQCGPZWdIahRBBNQWZ4Dafkw1H3MG1LM6a0F_WoDtHtdXxQQTv174t3OzWEewXvgXUCisDZo0AMPydMWe1dMmWcMlOYkuIAHUjoxOx1caSaGFKK2D_ZcKbm6FSJTs3RqWN0peLd39098f9kVQjySMDyR_cOo0rGoTdoXUSTlQ3uv-K_AXBnqOo</recordid><startdate>20130419</startdate><enddate>20130419</enddate><creator>Morishita, Hideaki</creator><creator>Eguchi, Satoshi</creator><creator>Kimura, Hirotaka</creator><creator>Sasaki, Junko</creator><creator>Sakamaki, Yuriko</creator><creator>Robinson, Michael L.</creator><creator>Sasaki, Takehiko</creator><creator>Mizushima, Noboru</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20130419</creationdate><title>Deletion of Autophagy-related 5 (Atg5) and Pik3c3 Genes in the Lens Causes Cataract Independent of Programmed Organelle Degradation</title><author>Morishita, Hideaki ; Eguchi, Satoshi ; Kimura, Hirotaka ; Sasaki, Junko ; Sakamaki, Yuriko ; Robinson, Michael L. ; Sasaki, Takehiko ; Mizushima, Noboru</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c509t-49d3fa10175d37af2c91b87ef2933dc47e7e93345730efd78c0e9e374c0e0c123</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Autophagy</topic><topic>Autophagy - genetics</topic><topic>Autophagy-Related Protein 5</topic><topic>Cataract</topic><topic>Cataract - embryology</topic><topic>Cataract - genetics</topic><topic>Cataract - pathology</topic><topic>Cell Biology</topic><topic>Class III Phosphatidylinositol 3-Kinases - genetics</topic><topic>Class III Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Crystallins - genetics</topic><topic>Crystallins - metabolism</topic><topic>Endocytosis - genetics</topic><topic>Lens</topic><topic>Lens Capsule, Crystalline - embryology</topic><topic>Lens Capsule, Crystalline - pathology</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Microtubule-Associated Proteins - genetics</topic><topic>Microtubule-Associated Proteins - metabolism</topic><topic>Organelle Degradation</topic><topic>Organelles - genetics</topic><topic>Organelles - metabolism</topic><topic>Organelles - pathology</topic><topic>Protein Degradation</topic><topic>Quality Control</topic><topic>Ubiquitin</topic><topic>Ubiquitinated Proteins - genetics</topic><topic>Ubiquitinated Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Morishita, Hideaki</creatorcontrib><creatorcontrib>Eguchi, Satoshi</creatorcontrib><creatorcontrib>Kimura, Hirotaka</creatorcontrib><creatorcontrib>Sasaki, Junko</creatorcontrib><creatorcontrib>Sakamaki, Yuriko</creatorcontrib><creatorcontrib>Robinson, Michael L.</creatorcontrib><creatorcontrib>Sasaki, Takehiko</creatorcontrib><creatorcontrib>Mizushima, Noboru</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Morishita, Hideaki</au><au>Eguchi, Satoshi</au><au>Kimura, Hirotaka</au><au>Sasaki, Junko</au><au>Sakamaki, Yuriko</au><au>Robinson, Michael L.</au><au>Sasaki, Takehiko</au><au>Mizushima, Noboru</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Deletion of Autophagy-related 5 (Atg5) and Pik3c3 Genes in the Lens Causes Cataract Independent of Programmed Organelle Degradation</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2013-04-19</date><risdate>2013</risdate><volume>288</volume><issue>16</issue><spage>11436</spage><epage>11447</epage><pages>11436-11447</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>The lens of the eye is composed of fiber cells, which differentiate from epithelial cells and undergo programmed organelle degradation during terminal differentiation. Although autophagy, a major intracellular degradation system, is constitutively active in these cells, its physiological role has remained unclear. We have previously shown that Atg5-dependent macroautophagy is not necessary for lens organelle degradation, at least during the embryonic period. Here, we generated lens-specific Atg5 knock-out mice and showed that Atg5 is not required for lens organelle degradation at any period of life. However, deletion of Atg5 in the lens results in age-related cataract, which is accompanied by accumulation of polyubiquitinated and oxidized proteins, p62, and insoluble crystallins, suggesting a defect in intracellular quality control. We also produced lens-specific Pik3c3 knock-out mice to elucidate the possible involvement of Atg5-independent alternative autophagy, which is proposed to be dependent on Pik3c3 (also known as Vps34), in lens organelle degradation. Deletion of Pik3c3 in the lens does not affect lens organelle degradation, but it leads to congenital cataract and a defect in lens development after birth likely due to an impairment of the endocytic pathway. Taken together, these results suggest that clearance of lens organelles is independent of macroautophagy. These findings also clarify the physiological role of Atg5 and Pik3c3 in quality control and development of the lens, respectively.
Background: The role of autophagy-dependent quality control in the lens remains unclear.
Results: Deletion of Atg5 and Pik3c3/Vps34 in the lens does not affect programmed organelle degradation but causes cataract and a developmental defect, respectively.
Conclusion: These genes are important for quality control and development of the lens.
Significance: This study provides new insights into biology and age-related pathology of the lens.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>23479732</pmid><doi>10.1074/jbc.M112.437103</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 0021-9258 |
ispartof | The Journal of biological chemistry, 2013-04, Vol.288 (16), p.11436-11447 |
issn | 0021-9258 1083-351X |
language | eng |
recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3630873 |
source | MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central; Alma/SFX Local Collection |
subjects | Animals Autophagy Autophagy - genetics Autophagy-Related Protein 5 Cataract Cataract - embryology Cataract - genetics Cataract - pathology Cell Biology Class III Phosphatidylinositol 3-Kinases - genetics Class III Phosphatidylinositol 3-Kinases - metabolism Crystallins - genetics Crystallins - metabolism Endocytosis - genetics Lens Lens Capsule, Crystalline - embryology Lens Capsule, Crystalline - pathology Mice Mice, Knockout Microtubule-Associated Proteins - genetics Microtubule-Associated Proteins - metabolism Organelle Degradation Organelles - genetics Organelles - metabolism Organelles - pathology Protein Degradation Quality Control Ubiquitin Ubiquitinated Proteins - genetics Ubiquitinated Proteins - metabolism |
title | Deletion of Autophagy-related 5 (Atg5) and Pik3c3 Genes in the Lens Causes Cataract Independent of Programmed Organelle Degradation |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-07T06%3A15%3A07IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Deletion%20of%20Autophagy-related%205%20(Atg5)%20and%20Pik3c3%20Genes%20in%20the%20Lens%20Causes%20Cataract%20Independent%20of%20Programmed%20Organelle%20Degradation&rft.jtitle=The%20Journal%20of%20biological%20chemistry&rft.au=Morishita,%20Hideaki&rft.date=2013-04-19&rft.volume=288&rft.issue=16&rft.spage=11436&rft.epage=11447&rft.pages=11436-11447&rft.issn=0021-9258&rft.eissn=1083-351X&rft_id=info:doi/10.1074/jbc.M112.437103&rft_dat=%3Cproquest_pubme%3E1338393872%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1338393872&rft_id=info:pmid/23479732&rft_els_id=S0021925820672192&rfr_iscdi=true |