{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:17:09Z","timestamp":1787876229483,"version":"build-2784847793"},"reference-count":51,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2022,9,13]],"date-time":"2022-09-13T00:00:00Z","timestamp":1663027200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"German Research Foundation (DFG)","doi-asserted-by":"publisher","award":["BU 1840\/5-3"],"award-info":[{"award-number":["BU 1840\/5-3"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>In the basal, proliferative layer of healthy skin, the mTOR complex 1 (mTORC1) is activated, thus regulating proliferation while preventing differentiation. When cells leave the proliferative, basal compartment, mTORC1 signaling is turned off, which allows differentiation. Under inflammatory conditions, this switch is hijacked by cytokines and prevents proper differentiation. It is currently unknown how mTORC1 is regulated to mediate these effects on keratinocyte differentiation. In other tissues, mTORC1 activity is controlled through various pathways via the tuberous sclerosis complex (TSC). Thus, we investigated whether the TS complex is regulated by proinflammatory cytokines and contributes to the pathogenesis of psoriasis. TNF-\u03b1 as well as IL-1\u03b2 induced the phosphorylation of TSC2, especially on S939 via the PI3-K\/AKT and MAPK pathway. Surprisingly, increased TSC2 phosphorylation could not be detected in psoriasis patients. Instead, TSC2 was strongly downregulated in lesional psoriatic skin compared to non-lesional skin of the same patients or healthy skin. In vitro inflammatory cytokines induced dissociation of TSC2 from the lysosome, followed by destabilization of the TS complex and degradation. Thus, we assume that in psoriasis, inflammatory cytokines induce strong TSC2 phosphorylation, which in turn leads to its degradation. Consequently, chronic mTORC1 activity impairs ordered keratinocyte differentiation and contributes to the phenotypical changes seen in the psoriatic epidermis.<\/jats:p>","DOI":"10.3390\/cells11182847","type":"journal-article","created":{"date-parts":[[2022,9,13]],"date-time":"2022-09-13T01:44:03Z","timestamp":1663033443000},"page":"2847","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["mTORC1 Activity in Psoriatic Lesions Is Mediated by Aberrant Regulation through the Tuberous Sclerosis Complex"],"prefix":"10.3390","volume":"11","author":[{"given":"Antonio","family":"Ferreri","sequence":"first","affiliation":[{"name":"Department of Dermatology, University Hospital, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Lang","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Hospital, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Kaufmann","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Hospital, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7838-197X","authenticated-orcid":false,"given":"Claudia","family":"Buerger","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Hospital, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"579","DOI":"10.3389\/fimmu.2018.00579","article-title":"Systemic Inflammation and Cardiovascular Comorbidity in Psoriasis Patients: Causes and Consequences","volume":"9","author":"Boehncke","year":"2018","journal-title":"Front. 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