A phosphorylation-driven functional switch in p62 bodies coordinates autophagic clearance of ubiquitinated proteins

A phosphorylation-driven functional switch in p62 bodies coordinates autophagic clearance of ubiquitinated proteins | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article A phosphorylation-driven functional switch in p62 bodies coordinates autophagic clearance of ubiquitinated proteins Masaaki Komatsu, Satoko Komatsu-Hirota, Keisuke Tabata, Yu-shin Sou, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6952753/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract p62/SQSTM1 self-assembles with polyubiquitin into liquid-like condensates (“p62 bodies”) that function as stress-signaling hubs and selective autophagy cargo. We show that TBK1-dependent phosphorylation at Ser403 acts as a tunable rheostat, inducing miniaturization and gelation of these condensates and licensing their rapid, piecemeal clearance. PP2A holoenzymes containing PPP2R5A/B/E, recruited via a KEAP1 bridge, counteract TBK1 by dephosphorylating Ser403. This phosphorylation within p62 bodies promotes a material transition from large, fluid droplets to compact, low-fluidity gels that efficiently capture LC3-positive isolation membranes and accelerate autophagic removal of ubiquitinated proteins. Homozygous p62S403E/S403E embryonic stem cells differentiate into post-mitotic neurons enriched in miniaturized, gel-like p62 bodies, suggesting that the same miniaturization–gelation mechanism maintains proteostasis in quiescent cells. Thus, a TBK1–PP2A switch at Ser403 regulates the material state of p62 condensates and serves as a central control point for p62-mediated proteostasis. Biological sciences/Cell biology/Autophagy Biological sciences/Biochemistry/Proteolysis/Protein quality control Biological sciences/Biophysics/Molecular biophysics/Supramolecular assembly Autophagy p62 body liquid-liquid phase separation proteostasis ubiquitin Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementalMovieS1.mov Supplementary Movie S1. 3D CLEM of p62-autophagosome structures in control cells. Three-dimensional CLEM of p62 bodies and associated autophagosomes in control siRNA-treated Huh-1 cells. Scale bar, 1092 nm. SupplementalMovieS2.mov Supplementary Movie S2. 3D CLEM of p62-autophagosome structures in PPP2R5s -knockdown cells. Three-dimensional CLEM of p62 bodies and associated autophagosomes in PPP2R5 siRNA-treated Huh-1 cells. Scale bar, 700 nm. SupplementalMovieS3.mov Supplementary Movie S3. 3D CLEM of p62–autophagosome structures in p62 -knockout cells expressing p62 S403E . Three-dimensional CLEM analysis of p62 bodies and their associated autophagosomes in p62 -deficient Huh-1 cells expressing the phosphomimetic mutant p62 S403E . Scale bar, 1000 nm. SupplementalMovieS4.mov Supplementary Movie S4. 3D CLEM of p62–autophagosome structures in p62 -knockout cells expressing p62 S403A. Three-dimensional CLEM analysis of p62 bodies and their associated autophagosomes in p62 -deficient Huh-1 cells expressing the non-phosphorylatable mutant p62 S403A . Scale bar, 1000 µm. SupplementaryFiguresNSMB.pdf Supplementary Figure S1. TBK1 localizes to p62 bodies (a) In vitro reconstitution assay. mCherry-p62 (10 µM) and SNAP-8×Ub were mixed with SNAP-TBK1 (Alexa Fluor 649) in the presence or absence of NBR1, NBR1 D50R , TAX1BP1, AZI2, and TBK1BP1. Samples were imaged by fluorescence microscopy. Scale bars, 2 µm. (b) Immunofluorescence microscopy. Huh-1 cells transfected with siRNAs targeting NBR1 , TAX1BP1 , AZI2 , or TBK1BP1 were stained with antibodies against p62 and TBK1. Scale bars, 5 µm. Supplementary Figure S2. Generation of knockout cell lines (a, b) Immunoblot analysis of TBK1 -knock-out (a) and PPP2R5A/B/E triple-knock-out (b) Huh-1 cells using the indicated antibodies. Results are representative of three independent experiments. Supplementary Figure S3. PPP2CA and PPP2R5A colocalize with p62 bodies Immunofluorescence microscopy of Huh-1 cells stained for PPP2CA and p62 (upper) or PPP2R5A and p62 (bottom). Scale bars, 5 µm. Supplementary Figure S4. The chemical shift perturbations upon the addition of KEAP1 in Figure 4b are plotted for each residue. Supplementary Figure S5. Immunoblot analysis of Huh-1 cells treated with 20 μM arsenite (As III) for 2 h, exposed to heat shock at 42 °C for 2 h, treated with 20 μg/mL puromycin for 2 h, or cultured in EBSS for 2 h. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6952753","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":478716857,"identity":"5ebf6a96-c560-4e99-935a-dcd4a77c7eff","order_by":0,"name":"Masaaki 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Scale bar, 1000 µm.\u003c/p\u003e","description":"","filename":"SupplementalMovieS4.mov","url":"https://assets-eu.researchsquare.com/files/rs-6952753/v1/67735e498a7b4e20fc8b713c.mov"},{"id":85889692,"identity":"8900fa74-673e-452b-a535-cb6d6092ef69","added_by":"auto","created_at":"2025-07-02 19:05:50","extension":"pdf","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":1117886,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Figure S1. TBK1 localizes to p62 bodies\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003ea\u003c/strong\u003e) \u003cem\u003eIn vitro\u003c/em\u003e reconstitution assay. mCherry-p62 (10 µM) and SNAP-8×Ub were mixed with SNAP-TBK1 (Alexa Fluor 649) in the presence or absence of NBR1, NBR1\u003csup\u003eD50R\u003c/sup\u003e, TAX1BP1, AZI2, and TBK1BP1. Samples were imaged by fluorescence microscopy. Scale bars, 2 µm. (\u003cstrong\u003eb\u003c/strong\u003e) Immunofluorescence microscopy. Huh-1 cells transfected with siRNAs targeting \u003cem\u003eNBR1\u003c/em\u003e, \u003cem\u003eTAX1BP1\u003c/em\u003e, \u003cem\u003eAZI2\u003c/em\u003e, or \u003cem\u003eTBK1BP1\u003c/em\u003e were stained with antibodies against p62 and TBK1. Scale bars, 5 µm.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary Figure S2. Generation of knockout cell lines\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(\u003cstrong\u003ea, b\u003c/strong\u003e) Immunoblot analysis of \u003cem\u003eTBK1\u003c/em\u003e-knock-out (a) and \u003cem\u003ePPP2R5A/B/E\u003c/em\u003e triple-knock-out (b) Huh-1 cells using the indicated antibodies. Results are representative of three independent experiments.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary Figure S3. PPP2CA and PPP2R5A colocalize with p62 bodies\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eImmunofluorescence microscopy of Huh-1 cells stained for PPP2CA and p62 (upper) or PPP2R5A and p62 (bottom). Scale bars, 5 µm.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary Figure S4.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe chemical shift perturbations upon the addition of KEAP1 in Figure 4b are plotted for each residue.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary Figure S5.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eImmunoblot analysis of Huh-1 cells treated with 20 μM arsenite (As\u003csup\u003e \u003c/sup\u003eIII) for 2 h, exposed to heat shock at 42 °C for 2 h, treated with 20 μg/mL puromycin for 2 h, or cultured in EBSS for 2 h.\u003c/p\u003e","description":"","filename":"SupplementaryFiguresNSMB.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6952753/v1/3c6e4a9ec236cbd86bba5f05.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"A phosphorylation-driven functional switch in p62 bodies coordinates autophagic clearance of ubiquitinated proteins","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Autophagy, p62 body, liquid-liquid phase separation, proteostasis, ubiquitin","lastPublishedDoi":"10.21203/rs.3.rs-6952753/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6952753/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"p62/SQSTM1 self-assembles with polyubiquitin into liquid-like condensates (“p62 bodies”) that function as stress-signaling hubs and selective autophagy cargo. We show that TBK1-dependent phosphorylation at Ser403 acts as a tunable rheostat, inducing miniaturization and gelation of these condensates and licensing their rapid, piecemeal clearance. PP2A holoenzymes containing PPP2R5A/B/E, recruited via a KEAP1 bridge, counteract TBK1 by dephosphorylating Ser403. This phosphorylation within p62 bodies promotes a material transition from large, fluid droplets to compact, low-fluidity gels that efficiently capture LC3-positive isolation membranes and accelerate autophagic removal of ubiquitinated proteins. Homozygous p62S403E/S403E embryonic stem cells differentiate into post-mitotic neurons enriched in miniaturized, gel-like p62 bodies, suggesting that the same miniaturization–gelation mechanism maintains proteostasis in quiescent cells. Thus, a TBK1–PP2A switch at Ser403 regulates the material state of p62 condensates and serves as a central control point for p62-mediated proteostasis.","manuscriptTitle":"A phosphorylation-driven functional switch in p62 bodies coordinates autophagic clearance of ubiquitinated proteins","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-02 19:05:45","doi":"10.21203/rs.3.rs-6952753/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1f007f99-3cef-4169-8c5b-370426ee42c5","owner":[],"postedDate":"July 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":50828333,"name":"Biological sciences/Cell biology/Autophagy"},{"id":50828334,"name":"Biological sciences/Biochemistry/Proteolysis/Protein quality control"},{"id":50828335,"name":"Biological sciences/Biophysics/Molecular biophysics/Supramolecular assembly"}],"tags":[],"updatedAt":"2025-07-25T14:31:12+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-02 19:05:45","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6952753","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6952753","identity":"rs-6952753","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}