mTORC1 Activity in Psoriatic Lesions Is Mediated by Aberrant Regulation through the Tuberous Sclerosis Complex

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 conditi...

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Published in:Cells (Basel, Switzerland) Switzerland), 2022-09, Vol.11 (18), p.2847
Main Authors: Ferreri, Antonio, Lang, Victoria, Kaufmann, Roland, Buerger, Claudia
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
AKT protein
Antibodies
Cell differentiation
Cell division
Cell proliferation
Cytokines
Dendritic cells
Development and progression
Epidermis
Growth factors
IL-1β
Inflammation
Kinases
MAP kinase
mTORC1
Phosphorylation
Proteins
Psoriasis
Skin diseases
Statistical analysis
TOR protein
Tuberous sclerosis
tuberous sclerosis complex
Tuberous Sclerosis Complex 2
Tumor necrosis factor-α
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Summary: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-α as well as IL-1β 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.
ISSN:2073-4409
2073-4409
DOI:10.3390/cells11182847