Inhibition of class I PI3K enhances chaperone-mediated autophagy
Chaperone-mediated autophagy (CMA) is the most selective form of lysosomal proteolysis, where individual peptides, recognized by a consensus motif, are translocated directly across the lysosomal membrane. CMA regulates the abundance of many disease-related proteins, with causative roles in neoplasia...
Gespeichert in:
| Veröffentlicht in: | The Journal of cell biology 2020-12, Vol.219 (12) |
|---|---|
| Hauptverfasser: | , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | |
|---|---|
| container_issue | 12 |
| container_start_page | |
| container_title | The Journal of cell biology |
| container_volume | 219 |
| creator | Endicott, S Joseph Ziemba, Zachary J Beckmann, Logan J Boynton, Dennis N Miller, Richard A |
| description | Chaperone-mediated autophagy (CMA) is the most selective form of lysosomal proteolysis, where individual peptides, recognized by a consensus motif, are translocated directly across the lysosomal membrane. CMA regulates the abundance of many disease-related proteins, with causative roles in neoplasia, neurodegeneration, hepatosteatosis, and other pathologies relevant to human health and aging. At the lysosomal membrane, CMA is inhibited by Akt-dependent phosphorylation of the CMA regulator GFAP. The INS-PI3K-PDPK1 pathway regulates Akt, but its role in CMA is unclear. Here, we report that inhibition of class I PI3K or PDPK1 activates CMA. In contrast, selective inhibition of class III PI3Ks does not activate CMA. Isolated liver lysosomes from mice treated with either of two orally bioavailable class I PI3K inhibitors, pictilisib or buparlisib, display elevated CMA activity, and decreased phosphorylation of lysosomal GFAP, with no change in macroautophagy. The findings of this study represent an important first step in repurposing class I PI3K inhibitors to modulate CMA in vivo. |
| doi_str_mv | 10.1083/jcb.202001031 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7557678</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2471033207</sourcerecordid><originalsourceid>FETCH-LOGICAL-c415t-c916bfcf59bb48bbc73873272635e05f807fa28720b78baa3867273cdb2cf5403</originalsourceid><addsrcrecordid>eNpdkb1PwzAQxS0EglIYWVEkFpbA-St2FwSq-KioBAPMlu06JFVqhzhB6n-PUaECphvud-_u3UPoBMMFBkkvl9ZcECAAGCjeQSPMGeQSM9hFIwCC8wkn_AAdxrgEACYY3UcHlAKTuKAjdD3zVW3qvg4-C2VmGx1jNsueZ_Qxc77S3rqY2Uq3rgve5Su3qHXvFpke-tBW-m19hPZK3UR3_F3H6PXu9mX6kM-f7mfTm3luGeZ9bie4MKUt-cQYJo2xgkpBiSAF5Q54KUGUmkhBwAhptKayEERQuzAkDTGgY3S10W0Hk66wzvedblTb1SvdrVXQtfrb8XWl3sKHEpyLQsgkcP4t0IX3wcVerepoXdNo78IQFWEcCiZ58bXr7B-6DEPnk71EifRoSkAkKt9Qtgsxdq7cHoNBfWWjUjZqm03iT3872NI_YdBPLaGI6g</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2471033207</pqid></control><display><type>article</type><title>Inhibition of class I PI3K enhances chaperone-mediated autophagy</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Alma/SFX Local Collection</source><creator>Endicott, S Joseph ; Ziemba, Zachary J ; Beckmann, Logan J ; Boynton, Dennis N ; Miller, Richard A</creator><creatorcontrib>Endicott, S Joseph ; Ziemba, Zachary J ; Beckmann, Logan J ; Boynton, Dennis N ; Miller, Richard A</creatorcontrib><description>Chaperone-mediated autophagy (CMA) is the most selective form of lysosomal proteolysis, where individual peptides, recognized by a consensus motif, are translocated directly across the lysosomal membrane. CMA regulates the abundance of many disease-related proteins, with causative roles in neoplasia, neurodegeneration, hepatosteatosis, and other pathologies relevant to human health and aging. At the lysosomal membrane, CMA is inhibited by Akt-dependent phosphorylation of the CMA regulator GFAP. The INS-PI3K-PDPK1 pathway regulates Akt, but its role in CMA is unclear. Here, we report that inhibition of class I PI3K or PDPK1 activates CMA. In contrast, selective inhibition of class III PI3Ks does not activate CMA. Isolated liver lysosomes from mice treated with either of two orally bioavailable class I PI3K inhibitors, pictilisib or buparlisib, display elevated CMA activity, and decreased phosphorylation of lysosomal GFAP, with no change in macroautophagy. The findings of this study represent an important first step in repurposing class I PI3K inhibitors to modulate CMA in vivo.</description><identifier>ISSN: 0021-9525</identifier><identifier>EISSN: 1540-8140</identifier><identifier>DOI: 10.1083/jcb.202001031</identifier><identifier>PMID: 33048163</identifier><language>eng</language><publisher>United States: Rockefeller University Press</publisher><subject>1-Phosphatidylinositol 3-kinase ; 3-Phosphoinositide-Dependent Protein Kinases - genetics ; 3-Phosphoinositide-Dependent Protein Kinases - metabolism ; Aging ; AKT protein ; Animals ; Autophagy ; Bioavailability ; Cell Death and Autophagy ; Disease ; Glial fibrillary acidic protein ; Glial Fibrillary Acidic Protein - genetics ; Glial Fibrillary Acidic Protein - metabolism ; Humans ; Inhibitors ; Kinases ; Lysosomes ; Lysosomes - genetics ; Lysosomes - metabolism ; Membranes ; Mice ; Molecular Chaperones - genetics ; Molecular Chaperones - metabolism ; Neurodegeneration ; NIH 3T3 Cells ; Peptides ; Phagocytosis ; Phosphatidylinositol 3-Kinases - genetics ; Phosphatidylinositol 3-Kinases - metabolism ; Phosphorylation ; Protein Homeostasis ; Proteolysis ; Proto-Oncogene Proteins c-akt - genetics ; Proto-Oncogene Proteins c-akt - metabolism</subject><ispartof>The Journal of cell biology, 2020-12, Vol.219 (12)</ispartof><rights>2020 Endicott et al.</rights><rights>Copyright Rockefeller University Press Dec 2020</rights><rights>2020 Endicott et al. 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c415t-c916bfcf59bb48bbc73873272635e05f807fa28720b78baa3867273cdb2cf5403</citedby><cites>FETCH-LOGICAL-c415t-c916bfcf59bb48bbc73873272635e05f807fa28720b78baa3867273cdb2cf5403</cites><orcidid>0000-0001-9266-9649 ; 0000-0002-8237-9784</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33048163$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Endicott, S Joseph</creatorcontrib><creatorcontrib>Ziemba, Zachary J</creatorcontrib><creatorcontrib>Beckmann, Logan J</creatorcontrib><creatorcontrib>Boynton, Dennis N</creatorcontrib><creatorcontrib>Miller, Richard A</creatorcontrib><title>Inhibition of class I PI3K enhances chaperone-mediated autophagy</title><title>The Journal of cell biology</title><addtitle>J Cell Biol</addtitle><description>Chaperone-mediated autophagy (CMA) is the most selective form of lysosomal proteolysis, where individual peptides, recognized by a consensus motif, are translocated directly across the lysosomal membrane. CMA regulates the abundance of many disease-related proteins, with causative roles in neoplasia, neurodegeneration, hepatosteatosis, and other pathologies relevant to human health and aging. At the lysosomal membrane, CMA is inhibited by Akt-dependent phosphorylation of the CMA regulator GFAP. The INS-PI3K-PDPK1 pathway regulates Akt, but its role in CMA is unclear. Here, we report that inhibition of class I PI3K or PDPK1 activates CMA. In contrast, selective inhibition of class III PI3Ks does not activate CMA. Isolated liver lysosomes from mice treated with either of two orally bioavailable class I PI3K inhibitors, pictilisib or buparlisib, display elevated CMA activity, and decreased phosphorylation of lysosomal GFAP, with no change in macroautophagy. The findings of this study represent an important first step in repurposing class I PI3K inhibitors to modulate CMA in vivo.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>3-Phosphoinositide-Dependent Protein Kinases - genetics</subject><subject>3-Phosphoinositide-Dependent Protein Kinases - metabolism</subject><subject>Aging</subject><subject>AKT protein</subject><subject>Animals</subject><subject>Autophagy</subject><subject>Bioavailability</subject><subject>Cell Death and Autophagy</subject><subject>Disease</subject><subject>Glial fibrillary acidic protein</subject><subject>Glial Fibrillary Acidic Protein - genetics</subject><subject>Glial Fibrillary Acidic Protein - metabolism</subject><subject>Humans</subject><subject>Inhibitors</subject><subject>Kinases</subject><subject>Lysosomes</subject><subject>Lysosomes - genetics</subject><subject>Lysosomes - metabolism</subject><subject>Membranes</subject><subject>Mice</subject><subject>Molecular Chaperones - genetics</subject><subject>Molecular Chaperones - metabolism</subject><subject>Neurodegeneration</subject><subject>NIH 3T3 Cells</subject><subject>Peptides</subject><subject>Phagocytosis</subject><subject>Phosphatidylinositol 3-Kinases - genetics</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Phosphorylation</subject><subject>Protein Homeostasis</subject><subject>Proteolysis</subject><subject>Proto-Oncogene Proteins c-akt - genetics</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><issn>0021-9525</issn><issn>1540-8140</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkb1PwzAQxS0EglIYWVEkFpbA-St2FwSq-KioBAPMlu06JFVqhzhB6n-PUaECphvud-_u3UPoBMMFBkkvl9ZcECAAGCjeQSPMGeQSM9hFIwCC8wkn_AAdxrgEACYY3UcHlAKTuKAjdD3zVW3qvg4-C2VmGx1jNsueZ_Qxc77S3rqY2Uq3rgve5Su3qHXvFpke-tBW-m19hPZK3UR3_F3H6PXu9mX6kM-f7mfTm3luGeZ9bie4MKUt-cQYJo2xgkpBiSAF5Q54KUGUmkhBwAhptKayEERQuzAkDTGgY3S10W0Hk66wzvedblTb1SvdrVXQtfrb8XWl3sKHEpyLQsgkcP4t0IX3wcVerepoXdNo78IQFWEcCiZ58bXr7B-6DEPnk71EifRoSkAkKt9Qtgsxdq7cHoNBfWWjUjZqm03iT3872NI_YdBPLaGI6g</recordid><startdate>20201207</startdate><enddate>20201207</enddate><creator>Endicott, S Joseph</creator><creator>Ziemba, Zachary J</creator><creator>Beckmann, Logan J</creator><creator>Boynton, Dennis N</creator><creator>Miller, Richard A</creator><general>Rockefeller University Press</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>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-9266-9649</orcidid><orcidid>https://orcid.org/0000-0002-8237-9784</orcidid></search><sort><creationdate>20201207</creationdate><title>Inhibition of class I PI3K enhances chaperone-mediated autophagy</title><author>Endicott, S Joseph ; Ziemba, Zachary J ; Beckmann, Logan J ; Boynton, Dennis N ; Miller, Richard A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c415t-c916bfcf59bb48bbc73873272635e05f807fa28720b78baa3867273cdb2cf5403</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>3-Phosphoinositide-Dependent Protein Kinases - genetics</topic><topic>3-Phosphoinositide-Dependent Protein Kinases - metabolism</topic><topic>Aging</topic><topic>AKT protein</topic><topic>Animals</topic><topic>Autophagy</topic><topic>Bioavailability</topic><topic>Cell Death and Autophagy</topic><topic>Disease</topic><topic>Glial fibrillary acidic protein</topic><topic>Glial Fibrillary Acidic Protein - genetics</topic><topic>Glial Fibrillary Acidic Protein - metabolism</topic><topic>Humans</topic><topic>Inhibitors</topic><topic>Kinases</topic><topic>Lysosomes</topic><topic>Lysosomes - genetics</topic><topic>Lysosomes - metabolism</topic><topic>Membranes</topic><topic>Mice</topic><topic>Molecular Chaperones - genetics</topic><topic>Molecular Chaperones - metabolism</topic><topic>Neurodegeneration</topic><topic>NIH 3T3 Cells</topic><topic>Peptides</topic><topic>Phagocytosis</topic><topic>Phosphatidylinositol 3-Kinases - genetics</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Phosphorylation</topic><topic>Protein Homeostasis</topic><topic>Proteolysis</topic><topic>Proto-Oncogene Proteins c-akt - genetics</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Endicott, S Joseph</creatorcontrib><creatorcontrib>Ziemba, Zachary J</creatorcontrib><creatorcontrib>Beckmann, Logan J</creatorcontrib><creatorcontrib>Boynton, Dennis N</creatorcontrib><creatorcontrib>Miller, Richard A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of cell biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Endicott, S Joseph</au><au>Ziemba, Zachary J</au><au>Beckmann, Logan J</au><au>Boynton, Dennis N</au><au>Miller, Richard A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of class I PI3K enhances chaperone-mediated autophagy</atitle><jtitle>The Journal of cell biology</jtitle><addtitle>J Cell Biol</addtitle><date>2020-12-07</date><risdate>2020</risdate><volume>219</volume><issue>12</issue><issn>0021-9525</issn><eissn>1540-8140</eissn><abstract>Chaperone-mediated autophagy (CMA) is the most selective form of lysosomal proteolysis, where individual peptides, recognized by a consensus motif, are translocated directly across the lysosomal membrane. CMA regulates the abundance of many disease-related proteins, with causative roles in neoplasia, neurodegeneration, hepatosteatosis, and other pathologies relevant to human health and aging. At the lysosomal membrane, CMA is inhibited by Akt-dependent phosphorylation of the CMA regulator GFAP. The INS-PI3K-PDPK1 pathway regulates Akt, but its role in CMA is unclear. Here, we report that inhibition of class I PI3K or PDPK1 activates CMA. In contrast, selective inhibition of class III PI3Ks does not activate CMA. Isolated liver lysosomes from mice treated with either of two orally bioavailable class I PI3K inhibitors, pictilisib or buparlisib, display elevated CMA activity, and decreased phosphorylation of lysosomal GFAP, with no change in macroautophagy. The findings of this study represent an important first step in repurposing class I PI3K inhibitors to modulate CMA in vivo.</abstract><cop>United States</cop><pub>Rockefeller University Press</pub><pmid>33048163</pmid><doi>10.1083/jcb.202001031</doi><orcidid>https://orcid.org/0000-0001-9266-9649</orcidid><orcidid>https://orcid.org/0000-0002-8237-9784</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0021-9525 |
| ispartof | The Journal of cell biology, 2020-12, Vol.219 (12) |
| issn | 0021-9525 1540-8140 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7557678 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | 1-Phosphatidylinositol 3-kinase 3-Phosphoinositide-Dependent Protein Kinases - genetics 3-Phosphoinositide-Dependent Protein Kinases - metabolism Aging AKT protein Animals Autophagy Bioavailability Cell Death and Autophagy Disease Glial fibrillary acidic protein Glial Fibrillary Acidic Protein - genetics Glial Fibrillary Acidic Protein - metabolism Humans Inhibitors Kinases Lysosomes Lysosomes - genetics Lysosomes - metabolism Membranes Mice Molecular Chaperones - genetics Molecular Chaperones - metabolism Neurodegeneration NIH 3T3 Cells Peptides Phagocytosis Phosphatidylinositol 3-Kinases - genetics Phosphatidylinositol 3-Kinases - metabolism Phosphorylation Protein Homeostasis Proteolysis Proto-Oncogene Proteins c-akt - genetics Proto-Oncogene Proteins c-akt - metabolism |
| title | Inhibition of class I PI3K enhances chaperone-mediated autophagy |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-03T22%3A29%3A14IST&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=Inhibition%20of%20class%20I%20PI3K%20enhances%20chaperone-mediated%20autophagy&rft.jtitle=The%20Journal%20of%20cell%20biology&rft.au=Endicott,%20S%20Joseph&rft.date=2020-12-07&rft.volume=219&rft.issue=12&rft.issn=0021-9525&rft.eissn=1540-8140&rft_id=info:doi/10.1083/jcb.202001031&rft_dat=%3Cproquest_pubme%3E2471033207%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=2471033207&rft_id=info:pmid/33048163&rfr_iscdi=true |