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Recent studies evidenced tau liquid\u2013liquid phase separation (LLPS) into droplets as an early event in tau pathogenesis with the potential to enhance aggregation. Tauopathies like AD are accompanied by sustained neuroinflammation and the release of alarmins at early stages of inflammatory responses encompass protective functions. The Ca<jats:sup>2+<\/jats:sup>\u2010binding S100B protein is an alarmin augmented in AD that was recently implicated as a proteostasis regulator acting as a chaperone\u2010type protein, inhibiting aggregation and toxicity through interactions of amyloidogenic clients with a regulatory surface exposed upon Ca<jats:sup>2+<\/jats:sup>\u2010binding. Here we expand the regulatory functions of S100B over protein condensation phenomena by reporting its Ca<jats:sup>2+<\/jats:sup>\u2010dependent activity as a modulator of tau LLPS induced by crowding agents (PEG) and metal ions (Zn<jats:sup>2+<\/jats:sup>). We observe that apo S100B has a negligible effect on PEG\u2010induced tau demixing but that Ca<jats:sup>2+<\/jats:sup>\u2010bound S100B prevents demixing, resulting in a shift of the phase diagram boundary to higher crowding concentrations. Also, while incubation with apo S100B does not compromise tau LLPS, addition of Ca<jats:sup>2+<\/jats:sup> results in a sharp decrease in turbidity, indicating that interactions with S100B\u2010Ca<jats:sup>2+<\/jats:sup> promote transition of tau to the mixed phase. Further, electrophoretic analysis and FLIM\u2010FRET studies revealed that S100B incorporates into tau liquid droplets, suggesting an important stabilizing and chaperoning role contributing to minimize toxic tau aggregates. Resorting to Alexa488\u2010labeled tau we observed that S100B\u2010Ca<jats:sup>2+<\/jats:sup> reduces the formation of tau fluorescent droplets, without compromising liquid\u2010like behavior and droplet fusion events. The Zn<jats:sup>2+<\/jats:sup>\u2010binding properties of S100B also contribute to regulate Zn<jats:sup>2+<\/jats:sup>\u2010promoted tau LLPS as droplets are decreased by Zn<jats:sup>2+<\/jats:sup> buffering by S100B, in addition to the Ca<jats:sup>2+<\/jats:sup>\u2010triggered interactions with tau. Altogether this work uncovers the versatility of S100B as a proteostasis regulator acting on protein condensation phenomena of relevance across the neurodegeneration continuum.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15756-fig-0005-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1111\/jnc.15756","type":"journal-article","created":{"date-parts":[[2023,1,9]],"date-time":"2023-01-09T10:46:44Z","timestamp":1673261204000},"page":"76-86","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Tau liquid\u2013liquid phase separation is modulated by the Ca<sup>2+<\/sup>\u2010switched chaperone activity of the <scp>S100B<\/scp> protein"],"prefix":"10.1111","volume":"166","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4791-5403","authenticated-orcid":false,"given":"Guilherme G.","family":"Moreira","sequence":"first","affiliation":[{"name":"BioISI\u2014Instituto de Biosistemas e Ci\u00eancias Integrativas, Faculdade de Ci\u00eancias Universidade de Lisboa  Lisbon Portugal"},{"name":"Departamento de Qu\u00edmica e Bioqu\u00edmica, Faculdade de Ci\u00eancias Universidade de Lisboa  Lisbon Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4662-6933","authenticated-orcid":false,"given":"Cl\u00e1udio M.","family":"Gomes","sequence":"additional","affiliation":[{"name":"BioISI\u2014Instituto de Biosistemas e Ci\u00eancias Integrativas, Faculdade de Ci\u00eancias Universidade de Lisboa  Lisbon Portugal"},{"name":"Departamento de Qu\u00edmica e Bioqu\u00edmica, Faculdade de Ci\u00eancias Universidade de Lisboa  Lisbon 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