Age-Associated Golgi Stress and Zinc Deficiency Exacerbate Hyperkeratosis Through MAPK Activation

Abstract

The Golgi apparatus, an intracellular organelle responsible for protein modification and vesicle transport, has been relatively understudied in the context of skin diseases. Our study yielded noteworthy findings establishing a solid correlation between Golgi dysfunction and hyperkeratosis. More precisely, we observed hyperkeratosis in patients with SCD-EDS, who exhibited zinc deficiency-mediated Golgi impairments, and we confirmed Golgi abnormalities in genomic data from 28 Psoriasis patients. To establish a direct connection between Golgi stress and hyperkeratosis, we experimentally induced Golgi stress using the Monensin Golgi stress inducer on the dorsal skin of mice. This led to hyperkeratosis, accompanied by the activation of the MAPK signaling pathway. We replicated this effect by topically applying a zinc-specific chelator, TPEN (N,N,Nʹ,Nʹ-tetrakis-(2-Pyridylmethyl)ethylenediamine), which heightened Golgi stress and MAPK signaling, thus substantiating that zinc deficiency induces Golgi stress. We also observed that aged mice, typically prone to zinc deficiency, exhibited increased Golgi stress in their skin. Reduced expression of the zinc transporter ZIP4 in the intestine suggested that diminished zinc absorption contributed to lower zinc levels in elderly skin. Recognizing the role of autophagy in Golgi maintenance, we applied an autophagy-facilitating patch to alleviate hyperkeratosis. This patch effectively reduced Golgi stress and ameliorated hyperkeratosis and skin regeneration. Our findings reveal the connection between age-related Golgi stress and hyperkeratosis exacerbation while demonstrating the potential for autophagy modulation as a promising avenue for hyperkeratosis treatment.