Raft-like lipid microdomains drive autophagy initiation via AMBRA1-ERLIN1 molecular association within MAMs
Mitochondria-associated membranes (MAMs) are essential communication subdomains of the endoplasmic reticulum (ER) that interact with mitochondria. We previously demonstrated that, upon macroautophagy/autophagy induction, AMBRA1 is recruited to the BECN1 complex and relocalizes to MAMs, where it regu...
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| Veröffentlicht in: | Autophagy 2021-09, Vol.17 (9), p.2528-2548 |
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| creator | Manganelli, Valeria Matarrese, Paola Antonioli, Manuela Gambardella, Lucrezia Vescovo, Tiziana Gretzmeier, Christine Longo, Agostina Capozzi, Antonella Recalchi, Serena Riitano, Gloria Misasi, Roberta Dengjel, Joern Malorni, Walter Fimia, Gian Maria Sorice, Maurizio Garofalo, Tina |
| description | Mitochondria-associated membranes (MAMs) are essential communication subdomains of the endoplasmic reticulum (ER) that interact with mitochondria. We previously demonstrated that, upon macroautophagy/autophagy induction, AMBRA1 is recruited to the BECN1 complex and relocalizes to MAMs, where it regulates autophagy by interacting with raft-like components. ERLIN1 is an endoplasmic reticulum lipid raft protein of the prohibitin family. However, little is known about its association with the MAM interface and its involvement in autophagic initiation. In this study, we investigated ERLIN1 association with MAM raft-like microdomains and its interaction with AMBRA1 in the regulation of the autophagic process. We show that ERLIN1 interacts with AMBRA1 at MAM raft-like microdomains, which represents an essential condition for autophagosome formation upon nutrient starvation, as demonstrated by knocking down ERLIN1 gene expression. Moreover, this interaction depends on the "integrity" of key molecules, such as ganglioside GD3 and MFN2. Indeed, knocking down ST8SIA1/GD3-synthase or MFN2 expression impairs AMBRA1-ERLIN1 interaction at the MAM level and hinders autophagy. In conclusion, AMBRA1-ERLIN1 interaction within MAM raft-like microdomains appears to be pivotal in promoting the formation of autophagosomes.
Abbreviations: ACSL4/ACS4: acyl-CoA synthetase long chain family member 4; ACTB/β-actin: actin beta; AMBRA1: autophagy and beclin 1 regulator 1; ATG14: autophagy related 14; BECN1: beclin 1; CANX: calnexin; Cy5: cyanine 5; ECL: enhanced chemiluminescence; ER: endoplasmic reticulum; ERLIN1/KE04: ER lipid raft associated 1; FB1: fumonisin B1; FE: FRET efficiency; FRET: Förster/fluorescence resonance energy transfer; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GD3: aNeu5Ac(2-8)aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1)ceramide; HBSS: Hanks' balanced salt solution; HRP: horseradish peroxidase; LMNB1: lamin B1; mAb: monoclonal antibody; MAMs: mitochondria-associated membranes; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MFN2: mitofusin 2; MTOR: mechanistic target of rapamycin kinase; MYC/cMyc: proto-oncogene, bHLH transcription factor; P4HB: prolyl 4-hydroxylase subunit beta; pAb: polyclonal antibody; PE: phycoerythrin; SCAP/SREBP: SREBF chaperone; SD: standard deviation; ST8SIA1: ST8 alpha-N-acetyl-neuraminide alpha-2,8 sialyltransferase 1; SQSTM1/p62: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; TUBB/beta-tubulin: tu |
| doi_str_mv | 10.1080/15548627.2020.1834207 |
| format | Article |
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Abbreviations: ACSL4/ACS4: acyl-CoA synthetase long chain family member 4; ACTB/β-actin: actin beta; AMBRA1: autophagy and beclin 1 regulator 1; ATG14: autophagy related 14; BECN1: beclin 1; CANX: calnexin; Cy5: cyanine 5; ECL: enhanced chemiluminescence; ER: endoplasmic reticulum; ERLIN1/KE04: ER lipid raft associated 1; FB1: fumonisin B1; FE: FRET efficiency; FRET: Förster/fluorescence resonance energy transfer; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GD3: aNeu5Ac(2-8)aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1)ceramide; HBSS: Hanks' balanced salt solution; HRP: horseradish peroxidase; LMNB1: lamin B1; mAb: monoclonal antibody; MAMs: mitochondria-associated membranes; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MFN2: mitofusin 2; MTOR: mechanistic target of rapamycin kinase; MYC/cMyc: proto-oncogene, bHLH transcription factor; P4HB: prolyl 4-hydroxylase subunit beta; pAb: polyclonal antibody; PE: phycoerythrin; SCAP/SREBP: SREBF chaperone; SD: standard deviation; ST8SIA1: ST8 alpha-N-acetyl-neuraminide alpha-2,8 sialyltransferase 1; SQSTM1/p62: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; TUBB/beta-tubulin: tubulin beta class I; ULK1: unc-51 like autophagy activating kinase 1; VDAC1/porin: voltage dependent anion channel 1.</description><identifier>ISSN: 1554-8627</identifier><identifier>EISSN: 1554-8635</identifier><identifier>DOI: 10.1080/15548627.2020.1834207</identifier><identifier>PMID: 33034545</identifier><language>eng</language><publisher>United States: Taylor & Francis</publisher><subject>AMBRA1 ; Autophagosomes - metabolism ; autophagy ; Autophagy - genetics ; ERLIN1 ; lipid rafts ; Lipids ; Mitochondria - metabolism ; mitochondria associated membranes ; Mitochondrial Membranes - metabolism ; Research Paper</subject><ispartof>Autophagy, 2021-09, Vol.17 (9), p.2528-2548</ispartof><rights>2020 Informa UK Limited, trading as Taylor & Francis Group 2020</rights><rights>2020 Informa UK Limited, trading as Taylor & Francis Group 2020 Informa UK Limited, trading as Taylor & Francis Group</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c468t-efa040ecabcf64c7a8aa4f46d9a19d29a7028d7f36fb39f59a951af66b4e68dd3</citedby><cites>FETCH-LOGICAL-c468t-efa040ecabcf64c7a8aa4f46d9a19d29a7028d7f36fb39f59a951af66b4e68dd3</cites><orcidid>0000-0003-3534-1502 ; 0000-0003-4438-3325 ; 0000-0002-9453-4614 ; 0000-0002-7568-4713</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8496542/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8496542/$$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/33034545$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Manganelli, Valeria</creatorcontrib><creatorcontrib>Matarrese, Paola</creatorcontrib><creatorcontrib>Antonioli, Manuela</creatorcontrib><creatorcontrib>Gambardella, Lucrezia</creatorcontrib><creatorcontrib>Vescovo, Tiziana</creatorcontrib><creatorcontrib>Gretzmeier, Christine</creatorcontrib><creatorcontrib>Longo, Agostina</creatorcontrib><creatorcontrib>Capozzi, Antonella</creatorcontrib><creatorcontrib>Recalchi, Serena</creatorcontrib><creatorcontrib>Riitano, Gloria</creatorcontrib><creatorcontrib>Misasi, Roberta</creatorcontrib><creatorcontrib>Dengjel, Joern</creatorcontrib><creatorcontrib>Malorni, Walter</creatorcontrib><creatorcontrib>Fimia, Gian Maria</creatorcontrib><creatorcontrib>Sorice, Maurizio</creatorcontrib><creatorcontrib>Garofalo, Tina</creatorcontrib><title>Raft-like lipid microdomains drive autophagy initiation via AMBRA1-ERLIN1 molecular association within MAMs</title><title>Autophagy</title><addtitle>Autophagy</addtitle><description>Mitochondria-associated membranes (MAMs) are essential communication subdomains of the endoplasmic reticulum (ER) that interact with mitochondria. We previously demonstrated that, upon macroautophagy/autophagy induction, AMBRA1 is recruited to the BECN1 complex and relocalizes to MAMs, where it regulates autophagy by interacting with raft-like components. ERLIN1 is an endoplasmic reticulum lipid raft protein of the prohibitin family. However, little is known about its association with the MAM interface and its involvement in autophagic initiation. In this study, we investigated ERLIN1 association with MAM raft-like microdomains and its interaction with AMBRA1 in the regulation of the autophagic process. We show that ERLIN1 interacts with AMBRA1 at MAM raft-like microdomains, which represents an essential condition for autophagosome formation upon nutrient starvation, as demonstrated by knocking down ERLIN1 gene expression. Moreover, this interaction depends on the "integrity" of key molecules, such as ganglioside GD3 and MFN2. Indeed, knocking down ST8SIA1/GD3-synthase or MFN2 expression impairs AMBRA1-ERLIN1 interaction at the MAM level and hinders autophagy. In conclusion, AMBRA1-ERLIN1 interaction within MAM raft-like microdomains appears to be pivotal in promoting the formation of autophagosomes.
Abbreviations: ACSL4/ACS4: acyl-CoA synthetase long chain family member 4; ACTB/β-actin: actin beta; AMBRA1: autophagy and beclin 1 regulator 1; ATG14: autophagy related 14; BECN1: beclin 1; CANX: calnexin; Cy5: cyanine 5; ECL: enhanced chemiluminescence; ER: endoplasmic reticulum; ERLIN1/KE04: ER lipid raft associated 1; FB1: fumonisin B1; FE: FRET efficiency; FRET: Förster/fluorescence resonance energy transfer; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GD3: aNeu5Ac(2-8)aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1)ceramide; HBSS: Hanks' balanced salt solution; HRP: horseradish peroxidase; LMNB1: lamin B1; mAb: monoclonal antibody; MAMs: mitochondria-associated membranes; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MFN2: mitofusin 2; MTOR: mechanistic target of rapamycin kinase; MYC/cMyc: proto-oncogene, bHLH transcription factor; P4HB: prolyl 4-hydroxylase subunit beta; pAb: polyclonal antibody; PE: phycoerythrin; SCAP/SREBP: SREBF chaperone; SD: standard deviation; ST8SIA1: ST8 alpha-N-acetyl-neuraminide alpha-2,8 sialyltransferase 1; SQSTM1/p62: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; TUBB/beta-tubulin: tubulin beta class I; ULK1: unc-51 like autophagy activating kinase 1; VDAC1/porin: voltage dependent anion channel 1.</description><subject>AMBRA1</subject><subject>Autophagosomes - metabolism</subject><subject>autophagy</subject><subject>Autophagy - genetics</subject><subject>ERLIN1</subject><subject>lipid rafts</subject><subject>Lipids</subject><subject>Mitochondria - metabolism</subject><subject>mitochondria associated membranes</subject><subject>Mitochondrial Membranes - metabolism</subject><subject>Research Paper</subject><issn>1554-8627</issn><issn>1554-8635</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU1vEzEQhlcIREvhJ4B85LKt119rXxBpVWilBKQIztbEH42pdx3s3VT592yUNIILJ1vjZ94Z-amq9w2-bLDEVw3nTArSXhJMppKkjOD2RXW-r9dSUP7ydCftWfWmlF8YUyEVeV2dUYop44yfV49L8EMdw6NDMWyCRV0wOdnUQegLsjlsHYJxSJs1POxQ6MMQYAipR9sAaLa4Xs6a-nY5v__WoC5FZ8YIGUEpyRy5pzCsQ48Ws0V5W73yEIt7dzwvqp9fbn_c3NXz71_vb2bz2jAhh9p5wAw7AyvjBTMtSADmmbAKGmWJghYTaVtPhV9R5bkCxRvwQqyYE9JaelF9OuRuxlXnrHH9kCHqTQ4d5J1OEPS_L31Y64e01ZIpwRmZAj4eA3L6Pboy6C4U42KE3qWxaMKYUly2HE8oP6DTr5WSnT-NabDei9LPovRelD6Kmvo-_L3jqevZzAR8PgCh9yl38JRytHqAXUzZZ-hNKJr-f8Yf6Gek9w</recordid><startdate>20210902</startdate><enddate>20210902</enddate><creator>Manganelli, Valeria</creator><creator>Matarrese, Paola</creator><creator>Antonioli, Manuela</creator><creator>Gambardella, Lucrezia</creator><creator>Vescovo, Tiziana</creator><creator>Gretzmeier, Christine</creator><creator>Longo, Agostina</creator><creator>Capozzi, Antonella</creator><creator>Recalchi, Serena</creator><creator>Riitano, Gloria</creator><creator>Misasi, Roberta</creator><creator>Dengjel, Joern</creator><creator>Malorni, Walter</creator><creator>Fimia, Gian Maria</creator><creator>Sorice, Maurizio</creator><creator>Garofalo, Tina</creator><general>Taylor & Francis</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>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-3534-1502</orcidid><orcidid>https://orcid.org/0000-0003-4438-3325</orcidid><orcidid>https://orcid.org/0000-0002-9453-4614</orcidid><orcidid>https://orcid.org/0000-0002-7568-4713</orcidid></search><sort><creationdate>20210902</creationdate><title>Raft-like lipid microdomains drive autophagy initiation via AMBRA1-ERLIN1 molecular association within MAMs</title><author>Manganelli, Valeria ; Matarrese, Paola ; Antonioli, Manuela ; Gambardella, Lucrezia ; Vescovo, Tiziana ; Gretzmeier, Christine ; Longo, Agostina ; Capozzi, Antonella ; Recalchi, Serena ; Riitano, Gloria ; Misasi, Roberta ; Dengjel, Joern ; Malorni, Walter ; Fimia, Gian Maria ; Sorice, Maurizio ; Garofalo, Tina</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c468t-efa040ecabcf64c7a8aa4f46d9a19d29a7028d7f36fb39f59a951af66b4e68dd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>AMBRA1</topic><topic>Autophagosomes - metabolism</topic><topic>autophagy</topic><topic>Autophagy - genetics</topic><topic>ERLIN1</topic><topic>lipid rafts</topic><topic>Lipids</topic><topic>Mitochondria - metabolism</topic><topic>mitochondria associated membranes</topic><topic>Mitochondrial Membranes - metabolism</topic><topic>Research Paper</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Manganelli, Valeria</creatorcontrib><creatorcontrib>Matarrese, Paola</creatorcontrib><creatorcontrib>Antonioli, Manuela</creatorcontrib><creatorcontrib>Gambardella, Lucrezia</creatorcontrib><creatorcontrib>Vescovo, Tiziana</creatorcontrib><creatorcontrib>Gretzmeier, Christine</creatorcontrib><creatorcontrib>Longo, Agostina</creatorcontrib><creatorcontrib>Capozzi, Antonella</creatorcontrib><creatorcontrib>Recalchi, Serena</creatorcontrib><creatorcontrib>Riitano, Gloria</creatorcontrib><creatorcontrib>Misasi, Roberta</creatorcontrib><creatorcontrib>Dengjel, Joern</creatorcontrib><creatorcontrib>Malorni, Walter</creatorcontrib><creatorcontrib>Fimia, Gian Maria</creatorcontrib><creatorcontrib>Sorice, Maurizio</creatorcontrib><creatorcontrib>Garofalo, Tina</creatorcontrib><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>Autophagy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Manganelli, Valeria</au><au>Matarrese, Paola</au><au>Antonioli, Manuela</au><au>Gambardella, Lucrezia</au><au>Vescovo, Tiziana</au><au>Gretzmeier, Christine</au><au>Longo, Agostina</au><au>Capozzi, Antonella</au><au>Recalchi, Serena</au><au>Riitano, Gloria</au><au>Misasi, Roberta</au><au>Dengjel, Joern</au><au>Malorni, Walter</au><au>Fimia, Gian Maria</au><au>Sorice, Maurizio</au><au>Garofalo, Tina</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Raft-like lipid microdomains drive autophagy initiation via AMBRA1-ERLIN1 molecular association within MAMs</atitle><jtitle>Autophagy</jtitle><addtitle>Autophagy</addtitle><date>2021-09-02</date><risdate>2021</risdate><volume>17</volume><issue>9</issue><spage>2528</spage><epage>2548</epage><pages>2528-2548</pages><issn>1554-8627</issn><eissn>1554-8635</eissn><abstract>Mitochondria-associated membranes (MAMs) are essential communication subdomains of the endoplasmic reticulum (ER) that interact with mitochondria. We previously demonstrated that, upon macroautophagy/autophagy induction, AMBRA1 is recruited to the BECN1 complex and relocalizes to MAMs, where it regulates autophagy by interacting with raft-like components. ERLIN1 is an endoplasmic reticulum lipid raft protein of the prohibitin family. However, little is known about its association with the MAM interface and its involvement in autophagic initiation. In this study, we investigated ERLIN1 association with MAM raft-like microdomains and its interaction with AMBRA1 in the regulation of the autophagic process. We show that ERLIN1 interacts with AMBRA1 at MAM raft-like microdomains, which represents an essential condition for autophagosome formation upon nutrient starvation, as demonstrated by knocking down ERLIN1 gene expression. Moreover, this interaction depends on the "integrity" of key molecules, such as ganglioside GD3 and MFN2. Indeed, knocking down ST8SIA1/GD3-synthase or MFN2 expression impairs AMBRA1-ERLIN1 interaction at the MAM level and hinders autophagy. In conclusion, AMBRA1-ERLIN1 interaction within MAM raft-like microdomains appears to be pivotal in promoting the formation of autophagosomes.
Abbreviations: ACSL4/ACS4: acyl-CoA synthetase long chain family member 4; ACTB/β-actin: actin beta; AMBRA1: autophagy and beclin 1 regulator 1; ATG14: autophagy related 14; BECN1: beclin 1; CANX: calnexin; Cy5: cyanine 5; ECL: enhanced chemiluminescence; ER: endoplasmic reticulum; ERLIN1/KE04: ER lipid raft associated 1; FB1: fumonisin B1; FE: FRET efficiency; FRET: Förster/fluorescence resonance energy transfer; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GD3: aNeu5Ac(2-8)aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1)ceramide; HBSS: Hanks' balanced salt solution; HRP: horseradish peroxidase; LMNB1: lamin B1; mAb: monoclonal antibody; MAMs: mitochondria-associated membranes; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MFN2: mitofusin 2; MTOR: mechanistic target of rapamycin kinase; MYC/cMyc: proto-oncogene, bHLH transcription factor; P4HB: prolyl 4-hydroxylase subunit beta; pAb: polyclonal antibody; PE: phycoerythrin; SCAP/SREBP: SREBF chaperone; SD: standard deviation; ST8SIA1: ST8 alpha-N-acetyl-neuraminide alpha-2,8 sialyltransferase 1; SQSTM1/p62: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; TUBB/beta-tubulin: tubulin beta class I; ULK1: unc-51 like autophagy activating kinase 1; VDAC1/porin: voltage dependent anion channel 1.</abstract><cop>United States</cop><pub>Taylor & Francis</pub><pmid>33034545</pmid><doi>10.1080/15548627.2020.1834207</doi><tpages>21</tpages><orcidid>https://orcid.org/0000-0003-3534-1502</orcidid><orcidid>https://orcid.org/0000-0003-4438-3325</orcidid><orcidid>https://orcid.org/0000-0002-9453-4614</orcidid><orcidid>https://orcid.org/0000-0002-7568-4713</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | AMBRA1 Autophagosomes - metabolism autophagy Autophagy - genetics ERLIN1 lipid rafts Lipids Mitochondria - metabolism mitochondria associated membranes Mitochondrial Membranes - metabolism Research Paper |
| title | Raft-like lipid microdomains drive autophagy initiation via AMBRA1-ERLIN1 molecular association within MAMs |
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