Loading…

Tau fibrils evade autophagy by excessive p62 coating and TAX1BP1 exclusion

The accumulation of protein aggregates is a hallmark of many diseases, including Alzheimer's disease. As a major pillar of the proteostasis network, autophagy mediates the degradation of protein aggregates. The autophagy cargo receptor p62 recognizes ubiquitin on proteins and cooperates with TA...

Full description

Saved in:
Bibliographic Details
Published in:Science advances 2024-06, Vol.10 (24), p.eadm8449
Main Authors: Ferrari, Luca, Bauer, Bernd, Qiu, Yue, Schuschnig, Martina, Klotz, Sigrid, Anrather, Dorothea, Juretschke, Thomas, Beli, Petra, Gelpi, Ellen, Martens, Sascha
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by
cites cdi_FETCH-LOGICAL-c276t-58b261998c5c02aa513e06c13a6ae694317d8d46d94ff2da28bf9f71c9de605f3
container_end_page
container_issue 24
container_start_page eadm8449
container_title Science advances
container_volume 10
creator Ferrari, Luca
Bauer, Bernd
Qiu, Yue
Schuschnig, Martina
Klotz, Sigrid
Anrather, Dorothea
Juretschke, Thomas
Beli, Petra
Gelpi, Ellen
Martens, Sascha
description The accumulation of protein aggregates is a hallmark of many diseases, including Alzheimer's disease. As a major pillar of the proteostasis network, autophagy mediates the degradation of protein aggregates. The autophagy cargo receptor p62 recognizes ubiquitin on proteins and cooperates with TAX1BP1 to recruit the autophagy machinery. Paradoxically, protein aggregates are not degraded in various diseases despite p62 association. Here, we reconstituted the recognition by the autophagy receptors of physiological and pathological Tau forms. Monomeric Tau recruits p62 and TAX1BP1 via the sequential actions of the chaperone and ubiquitylation machineries. In contrast, Tau fibrils from Alzheimer's disease brains are recognized by p62 but fail to recruit TAX1BP1. This failure is due to the masking of fibrils ubiquitin moieties by p62. Tau fibrils are resistant to deubiquitylation, and, thus, this nonproductive interaction of p62 with the fibrils is irreversible. Our results shed light on the mechanism underlying autophagy evasion by protein aggregates and their consequent accumulation in disease.
doi_str_mv 10.1126/sciadv.adm8449
format article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_11168460</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3067915189</sourcerecordid><originalsourceid>FETCH-LOGICAL-c276t-58b261998c5c02aa513e06c13a6ae694317d8d46d94ff2da28bf9f71c9de605f3</originalsourceid><addsrcrecordid>eNpVkc1LAzEQxYMoWtSrR8nRS2smm2STk1Txk4IeKngLs0m2Rra7dbNb7H9vpbXoaQbmN28e8wg5AzYC4OoyuYh-OUI_10KYPTLgWS6HXAq9_6c_IqcpfTDGQCglwRySo0xrJYU0A_I0xZ6WsWhjlWhYog8U-65ZvONsRYsVDV8upBSXgS4Up67BLtYzirWn0_EbXL_AD1H1KTb1CTkosUrhdFuPyevd7fTmYTh5vn-8GU-GjueqG0pdcAXGaCcd44gSssCUgwwVBmVEBrnXXihvRFlyj1wXpSlzcMYHxWSZHZOrje6iL-bBu1B3LVZ20cY5tivbYLT_J3V8t7NmaQFAaaHYWuFiq9A2n31InZ3H5EJVYR2aPtmMqdyABG3W6GiDurZJqQ3l7g4w-xOC3YRgtyGsF87_utvhvy_PvgEGToTh</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>3067915189</pqid></control><display><type>article</type><title>Tau fibrils evade autophagy by excessive p62 coating and TAX1BP1 exclusion</title><source>Science Online_科学在线</source><source>PubMed Central</source><creator>Ferrari, Luca ; Bauer, Bernd ; Qiu, Yue ; Schuschnig, Martina ; Klotz, Sigrid ; Anrather, Dorothea ; Juretschke, Thomas ; Beli, Petra ; Gelpi, Ellen ; Martens, Sascha</creator><creatorcontrib>Ferrari, Luca ; Bauer, Bernd ; Qiu, Yue ; Schuschnig, Martina ; Klotz, Sigrid ; Anrather, Dorothea ; Juretschke, Thomas ; Beli, Petra ; Gelpi, Ellen ; Martens, Sascha</creatorcontrib><description>The accumulation of protein aggregates is a hallmark of many diseases, including Alzheimer's disease. As a major pillar of the proteostasis network, autophagy mediates the degradation of protein aggregates. The autophagy cargo receptor p62 recognizes ubiquitin on proteins and cooperates with TAX1BP1 to recruit the autophagy machinery. Paradoxically, protein aggregates are not degraded in various diseases despite p62 association. Here, we reconstituted the recognition by the autophagy receptors of physiological and pathological Tau forms. Monomeric Tau recruits p62 and TAX1BP1 via the sequential actions of the chaperone and ubiquitylation machineries. In contrast, Tau fibrils from Alzheimer's disease brains are recognized by p62 but fail to recruit TAX1BP1. This failure is due to the masking of fibrils ubiquitin moieties by p62. Tau fibrils are resistant to deubiquitylation, and, thus, this nonproductive interaction of p62 with the fibrils is irreversible. Our results shed light on the mechanism underlying autophagy evasion by protein aggregates and their consequent accumulation in disease.</description><identifier>ISSN: 2375-2548</identifier><identifier>EISSN: 2375-2548</identifier><identifier>DOI: 10.1126/sciadv.adm8449</identifier><identifier>PMID: 38865459</identifier><language>eng</language><publisher>United States: American Association for the Advancement of Science</publisher><subject>Alzheimer Disease - metabolism ; Alzheimer Disease - pathology ; Autophagy ; Biochemistry ; Biomedicine and Life Sciences ; Diseases and Disorders ; Humans ; Intracellular Signaling Peptides and Proteins - metabolism ; Neoplasm Proteins ; Protein Aggregates ; Protein Binding ; SciAdv r-articles ; Sequestosome-1 Protein - metabolism ; tau Proteins - chemistry ; tau Proteins - metabolism ; Ubiquitin - metabolism ; Ubiquitination</subject><ispartof>Science advances, 2024-06, Vol.10 (24), p.eadm8449</ispartof><rights>Copyright © 2024 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). 2024 The Authors</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c276t-58b261998c5c02aa513e06c13a6ae694317d8d46d94ff2da28bf9f71c9de605f3</cites><orcidid>0000-0003-1677-2403 ; 0000-0003-0382-8084 ; 0000-0002-2015-0212 ; 0000-0003-3786-8199 ; 0000-0003-1934-157X ; 0000-0002-8926-6432 ; 0000-0003-3096-2852</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/PMC11168460/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11168460/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,2884,2885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38865459$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ferrari, Luca</creatorcontrib><creatorcontrib>Bauer, Bernd</creatorcontrib><creatorcontrib>Qiu, Yue</creatorcontrib><creatorcontrib>Schuschnig, Martina</creatorcontrib><creatorcontrib>Klotz, Sigrid</creatorcontrib><creatorcontrib>Anrather, Dorothea</creatorcontrib><creatorcontrib>Juretschke, Thomas</creatorcontrib><creatorcontrib>Beli, Petra</creatorcontrib><creatorcontrib>Gelpi, Ellen</creatorcontrib><creatorcontrib>Martens, Sascha</creatorcontrib><title>Tau fibrils evade autophagy by excessive p62 coating and TAX1BP1 exclusion</title><title>Science advances</title><addtitle>Sci Adv</addtitle><description>The accumulation of protein aggregates is a hallmark of many diseases, including Alzheimer's disease. As a major pillar of the proteostasis network, autophagy mediates the degradation of protein aggregates. The autophagy cargo receptor p62 recognizes ubiquitin on proteins and cooperates with TAX1BP1 to recruit the autophagy machinery. Paradoxically, protein aggregates are not degraded in various diseases despite p62 association. Here, we reconstituted the recognition by the autophagy receptors of physiological and pathological Tau forms. Monomeric Tau recruits p62 and TAX1BP1 via the sequential actions of the chaperone and ubiquitylation machineries. In contrast, Tau fibrils from Alzheimer's disease brains are recognized by p62 but fail to recruit TAX1BP1. This failure is due to the masking of fibrils ubiquitin moieties by p62. Tau fibrils are resistant to deubiquitylation, and, thus, this nonproductive interaction of p62 with the fibrils is irreversible. Our results shed light on the mechanism underlying autophagy evasion by protein aggregates and their consequent accumulation in disease.</description><subject>Alzheimer Disease - metabolism</subject><subject>Alzheimer Disease - pathology</subject><subject>Autophagy</subject><subject>Biochemistry</subject><subject>Biomedicine and Life Sciences</subject><subject>Diseases and Disorders</subject><subject>Humans</subject><subject>Intracellular Signaling Peptides and Proteins - metabolism</subject><subject>Neoplasm Proteins</subject><subject>Protein Aggregates</subject><subject>Protein Binding</subject><subject>SciAdv r-articles</subject><subject>Sequestosome-1 Protein - metabolism</subject><subject>tau Proteins - chemistry</subject><subject>tau Proteins - metabolism</subject><subject>Ubiquitin - metabolism</subject><subject>Ubiquitination</subject><issn>2375-2548</issn><issn>2375-2548</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNpVkc1LAzEQxYMoWtSrR8nRS2smm2STk1Txk4IeKngLs0m2Rra7dbNb7H9vpbXoaQbmN28e8wg5AzYC4OoyuYh-OUI_10KYPTLgWS6HXAq9_6c_IqcpfTDGQCglwRySo0xrJYU0A_I0xZ6WsWhjlWhYog8U-65ZvONsRYsVDV8upBSXgS4Up67BLtYzirWn0_EbXL_AD1H1KTb1CTkosUrhdFuPyevd7fTmYTh5vn-8GU-GjueqG0pdcAXGaCcd44gSssCUgwwVBmVEBrnXXihvRFlyj1wXpSlzcMYHxWSZHZOrje6iL-bBu1B3LVZ20cY5tivbYLT_J3V8t7NmaQFAaaHYWuFiq9A2n31InZ3H5EJVYR2aPtmMqdyABG3W6GiDurZJqQ3l7g4w-xOC3YRgtyGsF87_utvhvy_PvgEGToTh</recordid><startdate>20240614</startdate><enddate>20240614</enddate><creator>Ferrari, Luca</creator><creator>Bauer, Bernd</creator><creator>Qiu, Yue</creator><creator>Schuschnig, Martina</creator><creator>Klotz, Sigrid</creator><creator>Anrather, Dorothea</creator><creator>Juretschke, Thomas</creator><creator>Beli, Petra</creator><creator>Gelpi, Ellen</creator><creator>Martens, Sascha</creator><general>American Association for the Advancement of Science</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/0000-0003-1677-2403</orcidid><orcidid>https://orcid.org/0000-0003-0382-8084</orcidid><orcidid>https://orcid.org/0000-0002-2015-0212</orcidid><orcidid>https://orcid.org/0000-0003-3786-8199</orcidid><orcidid>https://orcid.org/0000-0003-1934-157X</orcidid><orcidid>https://orcid.org/0000-0002-8926-6432</orcidid><orcidid>https://orcid.org/0000-0003-3096-2852</orcidid></search><sort><creationdate>20240614</creationdate><title>Tau fibrils evade autophagy by excessive p62 coating and TAX1BP1 exclusion</title><author>Ferrari, Luca ; Bauer, Bernd ; Qiu, Yue ; Schuschnig, Martina ; Klotz, Sigrid ; Anrather, Dorothea ; Juretschke, Thomas ; Beli, Petra ; Gelpi, Ellen ; Martens, Sascha</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c276t-58b261998c5c02aa513e06c13a6ae694317d8d46d94ff2da28bf9f71c9de605f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Alzheimer Disease - metabolism</topic><topic>Alzheimer Disease - pathology</topic><topic>Autophagy</topic><topic>Biochemistry</topic><topic>Biomedicine and Life Sciences</topic><topic>Diseases and Disorders</topic><topic>Humans</topic><topic>Intracellular Signaling Peptides and Proteins - metabolism</topic><topic>Neoplasm Proteins</topic><topic>Protein Aggregates</topic><topic>Protein Binding</topic><topic>SciAdv r-articles</topic><topic>Sequestosome-1 Protein - metabolism</topic><topic>tau Proteins - chemistry</topic><topic>tau Proteins - metabolism</topic><topic>Ubiquitin - metabolism</topic><topic>Ubiquitination</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ferrari, Luca</creatorcontrib><creatorcontrib>Bauer, Bernd</creatorcontrib><creatorcontrib>Qiu, Yue</creatorcontrib><creatorcontrib>Schuschnig, Martina</creatorcontrib><creatorcontrib>Klotz, Sigrid</creatorcontrib><creatorcontrib>Anrather, Dorothea</creatorcontrib><creatorcontrib>Juretschke, Thomas</creatorcontrib><creatorcontrib>Beli, Petra</creatorcontrib><creatorcontrib>Gelpi, Ellen</creatorcontrib><creatorcontrib>Martens, Sascha</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>Science advances</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ferrari, Luca</au><au>Bauer, Bernd</au><au>Qiu, Yue</au><au>Schuschnig, Martina</au><au>Klotz, Sigrid</au><au>Anrather, Dorothea</au><au>Juretschke, Thomas</au><au>Beli, Petra</au><au>Gelpi, Ellen</au><au>Martens, Sascha</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tau fibrils evade autophagy by excessive p62 coating and TAX1BP1 exclusion</atitle><jtitle>Science advances</jtitle><addtitle>Sci Adv</addtitle><date>2024-06-14</date><risdate>2024</risdate><volume>10</volume><issue>24</issue><spage>eadm8449</spage><pages>eadm8449-</pages><issn>2375-2548</issn><eissn>2375-2548</eissn><abstract>The accumulation of protein aggregates is a hallmark of many diseases, including Alzheimer's disease. As a major pillar of the proteostasis network, autophagy mediates the degradation of protein aggregates. The autophagy cargo receptor p62 recognizes ubiquitin on proteins and cooperates with TAX1BP1 to recruit the autophagy machinery. Paradoxically, protein aggregates are not degraded in various diseases despite p62 association. Here, we reconstituted the recognition by the autophagy receptors of physiological and pathological Tau forms. Monomeric Tau recruits p62 and TAX1BP1 via the sequential actions of the chaperone and ubiquitylation machineries. In contrast, Tau fibrils from Alzheimer's disease brains are recognized by p62 but fail to recruit TAX1BP1. This failure is due to the masking of fibrils ubiquitin moieties by p62. Tau fibrils are resistant to deubiquitylation, and, thus, this nonproductive interaction of p62 with the fibrils is irreversible. Our results shed light on the mechanism underlying autophagy evasion by protein aggregates and their consequent accumulation in disease.</abstract><cop>United States</cop><pub>American Association for the Advancement of Science</pub><pmid>38865459</pmid><doi>10.1126/sciadv.adm8449</doi><orcidid>https://orcid.org/0000-0003-1677-2403</orcidid><orcidid>https://orcid.org/0000-0003-0382-8084</orcidid><orcidid>https://orcid.org/0000-0002-2015-0212</orcidid><orcidid>https://orcid.org/0000-0003-3786-8199</orcidid><orcidid>https://orcid.org/0000-0003-1934-157X</orcidid><orcidid>https://orcid.org/0000-0002-8926-6432</orcidid><orcidid>https://orcid.org/0000-0003-3096-2852</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 2375-2548
ispartof Science advances, 2024-06, Vol.10 (24), p.eadm8449
issn 2375-2548
2375-2548
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_11168460
source Science Online_科学在线; PubMed Central
subjects Alzheimer Disease - metabolism
Alzheimer Disease - pathology
Autophagy
Biochemistry
Biomedicine and Life Sciences
Diseases and Disorders
Humans
Intracellular Signaling Peptides and Proteins - metabolism
Neoplasm Proteins
Protein Aggregates
Protein Binding
SciAdv r-articles
Sequestosome-1 Protein - metabolism
tau Proteins - chemistry
tau Proteins - metabolism
Ubiquitin - metabolism
Ubiquitination
title Tau fibrils evade autophagy by excessive p62 coating and TAX1BP1 exclusion
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-24T09%3A43%3A31IST&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=Tau%20fibrils%20evade%20autophagy%20by%20excessive%20p62%20coating%20and%20TAX1BP1%20exclusion&rft.jtitle=Science%20advances&rft.au=Ferrari,%20Luca&rft.date=2024-06-14&rft.volume=10&rft.issue=24&rft.spage=eadm8449&rft.pages=eadm8449-&rft.issn=2375-2548&rft.eissn=2375-2548&rft_id=info:doi/10.1126/sciadv.adm8449&rft_dat=%3Cproquest_pubme%3E3067915189%3C/proquest_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c276t-58b261998c5c02aa513e06c13a6ae694317d8d46d94ff2da28bf9f71c9de605f3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=3067915189&rft_id=info:pmid/38865459&rfr_iscdi=true