KLHL24-Mediated Hair Follicle Stem Cells Structural Disruption Causes Alopecia.
J Invest Dermatol
; 142(8): 2079-2087.e8, 2022 08.
Article
em En
| MEDLINE
| ID: mdl-35066002
KLHL24 is an E3 ubiquitin ligase. Variants in the start codon of KLHL24 result in truncated KLHL24 protein lacking the initial 28 amino acids (KLHL24-ΔN28). KLHL24-ΔN28 is more stable than wild-type KLHL24 and causes excessive degradation of keratin 14, leading to epidermolysis bullosa. Patients with KLHL24-related epidermolysis bullosa usually develop alopecia, which is uncommon in patients with epidermolysis bullosa. The mechanisms by which KLHL24 variants cause alopecia is currently unclear. In this study, we show that KLHL24 regulates hair maintenance by mediating the stability of keratin 15. Using a Klhl24c.3G>T knock-in mouse model, we identify that KLHL24-ΔN28 disrupts the structure of hair follicle stem cells (HFSCs). Destructed HFSCs cannot anchor hairs and cause premature hair loss. Long-term destruction of HFSCs causes their exhaustion and hair follicle degeneration. Mechanically, KLHL24 mediates the ubiquitination and proteasomal degradation of keratin 15, an intermediate filament composing the HFSC cytoskeleton network. Keratin 15 is dramatically decreased in the skin of Klhl24c.3G>T mice and in patients with KLHL24-related epidermolysis bullosa. These findings show that KLHL24 plays a role in hair maintenance by regulating the cytoskeleton structure of HFSCs and highlight the importance of the ubiquitinâproteasome system in the stability of HFSCs.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Repressoras
/
Células-Tronco
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Epidermólise Bolhosa
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Folículo Piloso
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Alopecia
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
J Invest Dermatol
Ano de publicação:
2022
Tipo de documento:
Article