Chemical chaperones protect epidermolysis bullosa simplex keratinocytes from heat stress-induced keratin aggregation:: Involvement of heat shock proteins and MAP kinases
(English)In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747Article in journal (Refereed) Submitted
Epidermolysis bullosa simplex (EBS) is an inherited epithelial tissue fragility disorder due to mutations in keratin genes (KRT5 or KRT14), with no existing therapies. Aggregates of misfolded mutant keratins are seen in cultured keratinocytes from severe EBS patients. In some protein folding disorders such as cystic fibrosis and Alzheimer’s disease, chaperones and the ubiquitin-proteasome system modify disease severity, suggesting a novel therapeutic approach even for EBS. In this study, the effects of two chemical chaperones (trimethylamine-N oxide (TMAO) and 4-phenylbutyrate (4-PBA)) on heat stress-induced keratin aggregation responses were examined in newly and previously established immortalized control and EBS patient-derived keratinocyte cell lines. Heat-induced keratin-positive aggregates were observed in all EBS cells, which were most prominent in severe keratin-defective cell lines and less so in normal cells. The proportion of cells containing aggregates were dramatically reduced by TMAO and 4-PBA pretreatment. Furthermore, heat stress greatly induced MAP kinase activation (p38 and JNK) and increased Hsp70/Hsc70 expression, and TMAO was able to transiently modulate these effects. The results suggest that TMAO rescue may involve components of the endogenous chaperone and MAPK machineries, which may represent novel targets for the development of more effective treatments for EBS and other keratin-related genetic disorders.
EBS, keratinocytes, keratin, MAPK, immunostaining, Hsp, TMAO, 4-PBA
Medical and Health Sciences
Research subject Dermatology and Venerology
IdentifiersURN: urn:nbn:se:uu:diva-123064OAI: oai:DiVA.org:uu-123064DiVA: diva2:311762