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HSPs are highly regulated by post-translational modification, including deamidation, glycosylation, and phosphorylation. Among them, T148 phosphorylation has been shown to regulate the structural and functional characteristics of HSPB4 and underlie, in part, its neuroprotective capacity. We recently demonstrated that this phosphorylation is reduced in retinal tissues from patients with diabetic retinopathy, raising the question of its regulation during diseases. The kinase(s) responsible for regulating this phosphorylation, however, have yet to be identified. To this end, we employed a multi-tier strategy utilizing in vitro kinome profiling, bioinformatics, and chemoproteomics to predict and discover the kinases capable of phosphorylating T148. Several kinases were identified as being capable of specifically phosphorylating T148 in vitro, and further analysis highlighted mTORC2 as a particularly strong candidate. Altogether, our data demonstrate that the HSPB4-mTORC2 interaction is multi-faceted. Our data support the role of mTORC2 as a specific kinase phosphorylating HSPB4 at T148, but also provide evidence that the HSPB4 chaperone function further strengthens the interaction. This study addresses a critical gap in our understanding of the regulatory underpinnings of T148 phosphorylation-mediated neuroprotection.<\/jats:p>","DOI":"10.3390\/cells13232000","type":"journal-article","created":{"date-parts":[[2024,12,4]],"date-time":"2024-12-04T04:47:22Z","timestamp":1733287642000},"page":"2000","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Novel mTORC2\/HSPB4 Interaction: Role and Regulation of HSPB4 T148 Phosphorylation"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1666-9791","authenticated-orcid":false,"given":"Zachary B.","family":"Sluzala","sequence":"first","affiliation":[{"name":"Department of Ophthalmology & Visual Sciences, The University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0639-4501","authenticated-orcid":false,"given":"Yang","family":"Shan","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology & Visual Sciences, The University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynda","family":"Elghazi","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology & Visual Sciences, The University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilio L.","family":"C\u00e1rdenas","sequence":"additional","affiliation":[{"name":"Interdepartmental Program in Medicinal Chemistry, The University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7528-6963","authenticated-orcid":false,"given":"Angelina","family":"Hamati","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology & Visual Sciences, The University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda L.","family":"Garner","sequence":"additional","affiliation":[{"name":"Interdepartmental Program in Medicinal Chemistry, The University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3956-1908","authenticated-orcid":false,"given":"Patrice E.","family":"Fort","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology & Visual Sciences, The University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Department of Molecular & Integrative Physiology, The University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1379\/1466-1268(2003)8<53:THGECS>2.0.CO;2","article-title":"The human genome encodes 10 \u03b1-crystallin\u2013related small heat shock proteins: HspB1\u201310","volume":"8","author":"Franck","year":"2003","journal-title":"Cell Stress Chaperones"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1128\/MMBR.66.1.64-93.2002","article-title":"\u03b1-Crystallin-Type Heat Shock Proteins: Socializing Minichaperones in the Context of a Multichaperone Network","volume":"66","author":"Narberhaus","year":"2002","journal-title":"Microbiol. 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