{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:31:45Z","timestamp":1790832705246,"version":"4.1.0"},"reference-count":57,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,6,20]],"date-time":"2022-06-20T00:00:00Z","timestamp":1655683200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences of the National Institutes of Health","doi-asserted-by":"publisher","award":["SC3GM121226"],"award-info":[{"award-number":["SC3GM121226"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>HSPA1A is a molecular chaperone that regulates the survival of stressed and cancer cells. In addition to its cytosolic pro-survival functions, HSPA1A also localizes and embeds in the plasma membrane (PM) of stressed and tumor cells. Membrane-associated HSPA1A exerts immunomodulatory functions and renders tumors resistant to standard therapies. Therefore, understanding and manipulating HSPA1A\u2019s surface presentation is a promising therapeutic. However, HSPA1A\u2019s pathway to the cell surface remains enigmatic because this protein lacks known membrane localization signals. Considering that HSPA1A binds to lipids, like phosphatidylserine (PS) and monophosphorylated phosphoinositides (PIPs), we hypothesized that this interaction regulates HSPA1A\u2019s PM localization and anchorage. To test this hypothesis, we subjected human cell lines to heat shock, depleted specific lipid targets, and quantified HSPA1A\u2019s PM localization using confocal microscopy and cell surface biotinylation. These experiments revealed that co-transfection of HSPA1A with lipid-biosensors masking PI(4)P and PI(3)P significantly reduced HSPA1A\u2019s heat-induced surface presentation. Next, we manipulated the cellular lipid content using ionomycin, phenyl arsine oxide (PAO), GSK-A1, and wortmannin. These experiments revealed that HSPA1A\u2019s PM localization was unaffected by ionomycin but was significantly reduced by PAO, GSK-A1, and wortmannin, corroborating the findings obtained by the co-transfection experiments. We verified these results by selectively depleting PI(4)P and PI(4,5)P2 using a rapamycin-induced phosphatase system. Our findings strongly support the notion that HSPA1A\u2019s surface presentation is a multifaceted lipid-driven phenomenon controlled by the binding of the chaperone to specific endosomal and PM lipids.<\/jats:p>","DOI":"10.3390\/biom12060856","type":"journal-article","created":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T01:43:27Z","timestamp":1655775807000},"page":"856","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Phosphatidylinositol Monophosphates Regulate the Membrane Localization of HSPA1A, a Stress-Inducible 70-kDa Heat Shock Protein"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9533-0410","authenticated-orcid":false,"given":"Larissa","family":"Smulders","sequence":"first","affiliation":[{"name":"Department of Biological Science, Center for Applied Biotechnology Studies, and Center for Computational and Applied Mathematics, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, CA 92834, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9722-9829","authenticated-orcid":false,"given":"Rachel","family":"Altman","sequence":"additional","affiliation":[{"name":"Department of Biological Science, Center for Applied Biotechnology Studies, and Center for Computational and Applied Mathematics, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, CA 92834, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Briseno","sequence":"additional","affiliation":[{"name":"Department of Biological Science, Center for Applied Biotechnology Studies, and Center for Computational and Applied Mathematics, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, CA 92834, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alireza","family":"Saatchi","sequence":"additional","affiliation":[{"name":"Department of Biological Science, Center for Applied Biotechnology Studies, and Center for Computational and Applied Mathematics, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, CA 92834, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie","family":"Wallace","sequence":"additional","affiliation":[{"name":"Department of Biological Science, Center for Applied Biotechnology Studies, and Center for Computational and Applied Mathematics, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, CA 92834, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maha","family":"AlSebaye","sequence":"additional","affiliation":[{"name":"Department of Biological Science, Center for Applied Biotechnology Studies, and Center for Computational and Applied Mathematics, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, CA 92834, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5443-7863","authenticated-orcid":false,"given":"Robert V.","family":"Stahelin","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry and Molecular Pharmacology and the Purdue University Cancer Center, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5633-1883","authenticated-orcid":false,"given":"Nikolas","family":"Nikolaidis","sequence":"additional","affiliation":[{"name":"Department of Biological Science, Center for Applied Biotechnology Studies, and Center for Computational and Applied Mathematics, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, CA 92834, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1146\/annurev.ge.22.120188.003215","article-title":"The heat-shock proteins","volume":"22","author":"Lindquist","year":"1988","journal-title":"Annu. 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