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Review
. 2024 May 17:17:1133-1144.
doi: 10.2147/CCID.S459070. eCollection 2024.

Endoplasmic Reticulum Dysfunction: An Emerging Mechanism of Vitiligo Pathogenesis

Yongyi Xie #  1 , Nanhui Wu #  1 , Suwei Tang #  1 , Zhiyu Zhou  1 , Jiashe Chen  1 , Jie Li  1 , Fei Wu  1 , Mingyuan Xu  1 , Xiaoxiang Xu  1 , Yeqiang Liu  1 , Xin Ma  1   2
Affiliations
Review

Endoplasmic Reticulum Dysfunction: An Emerging Mechanism of Vitiligo Pathogenesis

Yongyi Xie et al. Clin Cosmet Investig Dermatol. .

Abstract

The endoplasmic reticulum (ER) is the main site of protein synthesis, transport, and modification. Its abnormal status has now emerged as an established cause of many pathological processes, such as tumors and autoimmune diseases. Recent studies also demonstrated that the defective functions of ER may lead to pigmentary diseases. Vitiligo is a depigmenting ailment skin disorder whose pathogenesis is now found to be associated with ER. However, the detailed mechanism is still unclear. In this review, we try to link the association between ER with its inter- and intra-organellar interactions in vitiligo pathogenesis and focus on the function, mechanism, and clinical potential of ER with vitiligo. Expand ER is found in melanocytes of vitiligo and ER stress (ERS) might be a bridge between oxidative stress and innate and adaptive immunity. Meanwhile, the tight association between ER and mitochondria or melanosomes in organelles levels, as well as genes and cytokines, is the new paradigm in the pathogenesis of vitiligo. This undoubtedly adds a new aspect to the understanding of vitiligo, facilitating the design of targeted therapies for vitiligo.

Keywords: cellular interactions; endoplasmic reticulum; organelles; oxidative stress; vitiligo.

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Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Schematic overview of unfolded protein response (UPR). When faced with stress conditions, the level of misfold or unfold proteins increases in the endoplasmic reticulum (ER) lumen and promotes recruitment of BiP. And then, three ER stress sensor IRE1, PERK, and ATF6 are activated. Active IRE1 triggers XBP1u mRNA, the unconventional splicing, to produce active transcription factor sXBP1. Active PERK promotes phosphorylation of elF2αleading to translation of ATF4 and CHOP. Translocation of ATF6 to the Golgi and proteolytic cleavage result in transcriptionally active form. Activation of these pathways trigger downstream transcriptional machinery resulting in expression of target genes associated with lipid metabolism, immune, inflammatory response, and differentiation, as well as structural/ functional expansion of ER and ERAD to overcome the stress conditions. Otherwise, persistent or excessive ERS might changes Ca2+ concentration inside mitochondria and mediate cell death pathway.
Figure 2
Figure 2
Pigmentary diseases related to ER homeostasis. Dysfunction of ER is associated with multiple diseases. Pigmentary disorders can manifest as abnormal pigmentation of the skin, eyes, and hair. These different kind of pigmentary diseases which are potentially relevant to ER dysfunction are listed.
Figure 3
Figure 3
The cellular and intracellular interactions of ER in pathogenesis of vitiligo. The characteristic of vitiligo is melanocytes absence. Expanded ER can be seen in melanocytes and keratinocytes. The generation of ROS activates SIRT3-OPA1 and TRPM2, which cause Ca2+ released from ER to mitochondria. Both conditions cause mitochondrial fission and ultimately lead to apoptosis of melanocytes. The link between ER and melanosome might be associated with PMEL and melanin-related proteins in ER, such as tyrosinase ER retention. PMEL is synthesized in ER and ultimately transported melanosomes for fibril formation. But affected by Ca2+ homeostasis, improper maturation of PMEL fibrils and defected melanosome might also be involved in vitiligo. In addition, prolonged ERS could activate targeted genes and inflammatory reaction and increase the release of cytokines, which generates further ER stress and oxidative stress. CXCL16 could recruit CD8+ T cell, resulting in an anti-melanocyte autoimmune response.
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