Abstract
The term orthodisease defines human disorders in which the pathogenic gene has orthologs in model organism genomes. Yeasts have been instrumental for gaining insights into the molecular basis of many human disorders, particularly those resulting from impaired cellular metabolism. We and others have used yeasts as a model system to study the molecular basis of Hailey-Hailey disease (HHD), a human blistering skin disorder caused by haploinsufficiency of the gene ATP2C1 the orthologous of the yeast gene PMR1. We observed that K. lactis cells defective for PMR1 gene share several biological similarities with HHD derived keratinocytes. Based on the conservation of ATP2C1/PMR1 function from yeast to human, here we used a yeast-based assay to screen for molecules able to influence the pleiotropy associated with PMR1 deletion. We identified six compounds, Kaempferol, Indirubin, Lappaconite, Cyclocytidine, Azomycin and Nalidixic Acid that induced different major shape phenotypes in K. lactis. These include mitochondrial and the cell-wall morphology-related phenotypes. Interestingly, a secondary assay in mammalian cells confirmed activity for Kaempferol. Indeed, this compound was also active on human keratinocytes depleted of ATP2C1 function by siRNA-treatment used as an in-vitro model of HHD. We found that Kaempferol was a potent NRF2 regulator, strongly inducing its expression and its downstream target NQO1. In addition, Kaempferol could decrease oxidative stress of ATP2C1 defective keratinocytes, characterized by reduced NRF2-expression. Our results indicated that the activation of these pathways might provide protection to the HHD-skin cells. As oxidative stress plays pivotal roles in promoting the skin lesions of Hailey-Hailey, the NRF2 pathway could be a viable therapeutic target for HHD.
Highlights
Hailey-Hailey disease (HHD), called benign familial pemphigus, is an autosomal dominant blistering skin disorder, manifesting in the 3rd to 4th decades of life
We demonstrated the feasibility of using the yeast Kluyveromyces lactis for modeling Hailey-Hailey disease [21]
We have established that altered function of these factors plays an important role in the alteration observed in HHD-derived keratinocytes [7]. Both NOTCH1 and NRF2 factors are important determinant of skin homeostasis and we found that they are differentially regulated between normal and HHD-derived keratinocytes, as well as in HaCaT cells interfered for ATP2C1 function [7]
Summary
Hailey-Hailey disease (HHD), called benign familial pemphigus, is an autosomal dominant blistering skin disorder, manifesting in the 3rd to 4th decades of life. About 30% of the genes known to be involved in human diseases have a yeast ortholog [14,15] For these reasons, this simple organism is widely used for high-throughput genetic and small-molecule screens to find possible pharmacological drugs for many human diseases. We showed that, both in yeast cells and in the lesional-derived keratinocytes of HHD patients, the expression of this detoxifying gene is down-regulated [21]. Based on these observations, in this study we establish a yeast-based screening assay, designed to identify drugs that could be active against Hailey-Hailey disorder.
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