Abstract
The p63 gene encodes a master regulator of epidermal commitment, development, and differentiation. Heterozygous mutations in the C-terminal domain of the p63 gene can cause ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome, a life-threatening disorder characterized by skin fragility and severe, long-lasting skin erosions. Despite deep knowledge of p63 functions, little is known about mechanisms underlying disease pathology and possible treatments. Here, we show that multiple AEC-associated p63 mutations, but not those causative of other diseases, lead to thermodynamic protein destabilization, misfolding, and aggregation, similar to the known p53 gain-of-function mutants found in cancer. AEC mutant proteins exhibit impaired DNA binding and transcriptional activity, leading to dominant negative effects due to coaggregation with wild-type p63 and p73. Importantly, p63 aggregation occurs also in a conditional knock-in mouse model for the disorder, in which the mis-folded p63 mutant protein leads to severe epidermal defects. Variants of p63 that abolish aggregation of the mutant proteins are able to rescue p63’s transcriptional function in reporter assays as well as in a human fibroblast-to-keratinocyte conversion assay. Our studies reveal that AEC syndrome is a protein aggregation disorder and opens avenues for therapeutic intervention.
| Original language | English |
|---|---|
| Pages (from-to) | E906-E915 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 115 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - Jan 30 2018 |
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Keywords
- AEC syndrome
- mouse model
- p63
- protein aggregation
- skin
ASJC Scopus subject areas
- General
Cite this
Protein aggregation of the p63 transcription factor underlies severe skin fragility in AEC syndrome. / Russo, Claudia; Osterburg, Christian; Sirico, Anna; Antonini, Dario; Ambrosio, Raffaele; Würz, Julia Maren; Rinnenthal, Jörg; Ferniani, Marco; Kehrloesser, Sebastian; Schäfer, Birgit; Güntert, Peter; Sinha, Satrajit; Dötsch, Volker; Missero, Caterina.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 5, 30.01.2018, p. E906-E915.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Protein aggregation of the p63 transcription factor underlies severe skin fragility in AEC syndrome
AU - Russo, Claudia
AU - Osterburg, Christian
AU - Sirico, Anna
AU - Antonini, Dario
AU - Ambrosio, Raffaele
AU - Würz, Julia Maren
AU - Rinnenthal, Jörg
AU - Ferniani, Marco
AU - Kehrloesser, Sebastian
AU - Schäfer, Birgit
AU - Güntert, Peter
AU - Sinha, Satrajit
AU - Dötsch, Volker
AU - Missero, Caterina
PY - 2018/1/30
Y1 - 2018/1/30
N2 - The p63 gene encodes a master regulator of epidermal commitment, development, and differentiation. Heterozygous mutations in the C-terminal domain of the p63 gene can cause ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome, a life-threatening disorder characterized by skin fragility and severe, long-lasting skin erosions. Despite deep knowledge of p63 functions, little is known about mechanisms underlying disease pathology and possible treatments. Here, we show that multiple AEC-associated p63 mutations, but not those causative of other diseases, lead to thermodynamic protein destabilization, misfolding, and aggregation, similar to the known p53 gain-of-function mutants found in cancer. AEC mutant proteins exhibit impaired DNA binding and transcriptional activity, leading to dominant negative effects due to coaggregation with wild-type p63 and p73. Importantly, p63 aggregation occurs also in a conditional knock-in mouse model for the disorder, in which the mis-folded p63 mutant protein leads to severe epidermal defects. Variants of p63 that abolish aggregation of the mutant proteins are able to rescue p63’s transcriptional function in reporter assays as well as in a human fibroblast-to-keratinocyte conversion assay. Our studies reveal that AEC syndrome is a protein aggregation disorder and opens avenues for therapeutic intervention.
AB - The p63 gene encodes a master regulator of epidermal commitment, development, and differentiation. Heterozygous mutations in the C-terminal domain of the p63 gene can cause ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome, a life-threatening disorder characterized by skin fragility and severe, long-lasting skin erosions. Despite deep knowledge of p63 functions, little is known about mechanisms underlying disease pathology and possible treatments. Here, we show that multiple AEC-associated p63 mutations, but not those causative of other diseases, lead to thermodynamic protein destabilization, misfolding, and aggregation, similar to the known p53 gain-of-function mutants found in cancer. AEC mutant proteins exhibit impaired DNA binding and transcriptional activity, leading to dominant negative effects due to coaggregation with wild-type p63 and p73. Importantly, p63 aggregation occurs also in a conditional knock-in mouse model for the disorder, in which the mis-folded p63 mutant protein leads to severe epidermal defects. Variants of p63 that abolish aggregation of the mutant proteins are able to rescue p63’s transcriptional function in reporter assays as well as in a human fibroblast-to-keratinocyte conversion assay. Our studies reveal that AEC syndrome is a protein aggregation disorder and opens avenues for therapeutic intervention.
KW - AEC syndrome
KW - mouse model
KW - p63
KW - protein aggregation
KW - skin
UR - http://www.scopus.com/inward/record.url?scp=85041180176&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85041180176&partnerID=8YFLogxK
U2 - 10.1073/pnas.1713773115
DO - 10.1073/pnas.1713773115
M3 - Article
AN - SCOPUS:85041180176
VL - 115
SP - E906-E915
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 5
ER -