Titolo della tesi: Loss of ATP2C1 function promotes endocytosis and degradation of NOTCH1: implications for Hailey-Hailey- disease.
Hailey-Hailey Disease (HHD) is a rare autosomal dominantly inherited
disorder caused by mutations in the ATP2C1 gene that encodes an
adenosine triphosphate (ATP)-powered calcium channel pump. HHD is
characterized by impaired epidermal cell-to-cell adhesion and defective
keratinocyte growth/differentiation. The mechanism by which mutant
ATP2C1 causes HHD is unknown and current treatments for affected
individuals do not address the underlying defects and are ineffective.
NOTCH signaling is a direct determinant of keratinocyte growth and
differentiation. We found that loss of ATP2C1 leads to impaired NOTCH1
signaling, thus deregulation of the NOTCH signaling response is therefore
likely to contribute to HHD manifestation. NOTCH1 is a transmembrane
receptor and upon ligand binding, NOTCH intracellular domain (NICD)
translocates to the nucleus activating its target genes. In the context of HHD
we found that loss of ATP2C1 function promotes upregulation of the active
NOTCH1 protein, (NICD-Val1744). Here, deeply exploring this aspect, we
observed that NOTCH1 activation is not associated with the transcriptional
enhancement of its targets. Moreover, in agreement with these results, we
found a cytoplasmic localization of NICD-Val1744. We have also observed
that ATP2C1-loss is associated with the degradation of NICD-Val1744
through the lysosomal/proteasome pathway. These results show that
ATP2C1-loss could promote a mechanism by which NOTCH1 is
endocytosed and degraded by the cell membrane. The deregulation of this
phenomenon, finely regulated in physiological conditions, could in HHD
lead to the deregulation of NOTCH1 with alteration of skin homeostasis
and disease manifestation.