Role of autophagy-related gene 7 in the skin of vitiligo patients

Shimaa Mohammed Hamed; Rehab Monir Samaka; Mohammed Ahmed Basha

doi:10.4103/ejdv.ejdv_15_18

SYSTEMATIC REVIEW

Year : 2019 | Volume : 39 | Issue : 1 | Page : 1-4

Role of autophagy-related gene 7 in the skin of vitiligo patients

Shimaa Mohammed Hamed¹, Rehab Monir Samaka², Mohammed Ahmed Basha³
¹ Dermatology, Andrology and STDS Department, Faculty of Medicine, Menoufia University, Egypt
² Professor of Pathology, Faculty of Medicine, Menoufia University, Egypt
³ Professor of Dermatology, Andrology and STDS, Faculty of Medicine, Menoufia University, Egypt

Date of Submission	21-Mar-2018
Date of Acceptance	16-Jun-2018
Date of Web Publication	28-Jan-2019

Correspondence Address:
Shimaa Mohammed Hamed
Dermatology, Andrology and STDS Department, Faculty of Medicine, Menoufia University, 32951
Egypt

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/ejdv.ejdv_15_18

Abstract

Objectives To perform a systematic review to summarize the role of autophagy-related gene 7 (ATG7) and autophagy in vitiligo.
Background Vitiligo is an acquired autoimmune pigmentary disorder due to loss of functional melanocytes. Colocalization studies revealed that the autophagy-related gene 7 has a role in the pathogenesis of vitiligo.
Materials and methods Medline databases (Google Scholar, Medscape, ScienceDirect) and all materials published in English language available on the internet from 2007 to 2018. The search was performed on March 2018. All the studies were independently assessed for inclusion. They were included if they fulfilled the following criteria: published in English language, published in peer-reviewed journals, focused on the role of ATG7 in vitiligo. The initial search presented 38 articles which studied the role of ATG7 in vitiligo. If the studies did not fulfill the inclusion criteria, they were excluded such as studies on ATG7 in systemic diseases or skin diseases other than vitiligo, report without peer review, not within the national research program, letters/comments/editorials/news. Comparisons were made by a structured review with the results tabulated.
Results In total, four potentially relevant publications were included; there was an association between vitiligo and autophagy marker ATG7. This association was due to premature senescence of melanocytes due to the accumulation of products of oxidative damage leading to pigment dilution.
Conclusion Autophagy marker-related gene 7 has a role in the pathogenesis of vitiligo.

Keywords: Autophagy-related gene 7, melanocytes, vitiligo

How to cite this article:
Hamed SM, Samaka RM, Basha MA. Role of autophagy-related gene 7 in the skin of vitiligo patients. Egypt J Dermatol Venerol 2019;39:1-4

How to cite this URL:
Hamed SM, Samaka RM, Basha MA. Role of autophagy-related gene 7 in the skin of vitiligo patients. Egypt J Dermatol Venerol [serial online] 2019 [cited 2023 Mar 31];39:1-4. Available from: http://www.ejdv.eg.net/text.asp?2019/39/1/1/250813

Introduction

Vitiligo is an acquired autoimmune pigmentary disorder due to loss of functional melanocytes (MCs) [1]. Its estimated prevalence is 1% of the population worldwide. The disease seems to affect all skin types and ethnic groups equally [2].

Vitiligo is frequently associated with autoimmune disorders such as thyroid abnormalities, rheumatoid arthritis, adult-onset type I diabetes mellitus, pernicious anemia, alopecia areata, and autoimmune polyglandular syndromes [3].

Autophagy, literally meaning ‘self-eating,’ is an intracellular catabolic process of delivering cytosol and/or its specific content to the lysosomes for degradation. The resulting macromolecular constituents are then recycled and utilized by the cells [4].

Genetic screening of autophagy-deficient mutants in yeast provides us with almost 40 ATG (autophagy-related genes) [5].

Autophagy-related gene 7 (ATG7) is an E1-like enzyme that activates and forms a thioester bond with two Ubls, ATG8 and ATG12 [6]. Defects in autophagy have implications for MC survival and manifestations of skin pigmentary disorders. Zhang et al. [7] have shown that mouse MCs lacking the autophagy protein ATG7 undergo premature senescence in vitro and accumulate products of oxidative damage, despite activation of the redox response.

In view of this complex mystery with a serious psychological impact on the quality of life in patients with vitiligo, it may be logic to study the possible role of ATG7 trying to through light on its impact on vitiligo.

Materials and methods

Search strategy

We reviewed papers on the relation between vitiligo and autophagic marker ATG7 from Medline databases such as Google Scholar, Medscape, ScienceDirect and also from materials available on the internet from 2007 to 2017. The search terms used were ATG7, MCs, and vitiligo.

Study selection

All the studies were independently assessed for inclusion. They were included if they fulfilled the following criteria.

Inclusion criteria of the published studies:

Explain autophagy as a mechanism of vitiligo.
ATG7 assay in vitiligo by any technique.
Published in English language.
Published in peer-reviewed journals.

If a study had several publications on certain aspects we used the latest publication giving the most relevant data.

Data extraction

If the studies did not fulfill the above criteria, they were excluded.

The analyzed publications were evaluated according to evidence-based medicine (EBM) criteria using the classification of the US Preventive Services Task Force and UK National Health Service protocol for EBM in addition to the evidence pyramid.

US Preventive Services Task Force:

Level I: evidence obtained from at least one properly designed randomized controlled trial.
Level II-1: evidence obtained from well-designed controlled trails without randomization.
Level II-2: evidence obtained from well-designed cohort or case–control analytic studies preferably from more than one center or research group.
Level II-3: evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence.
Level III: opinions of respected authorities, based on clinical experiences, descriptive studies, or reports of expert committees.

Study quality assessment included whether ethical approval was gained, eligibility criteria specified, appropriate controls, adequate information and defined assessment measures.

Quality assessment

The quality of all the studies was assessed. Important factors included the study design, attainment of ethical approval, evidence of power calculation, specified eligibility criteria, appropriate controls, adequate information, and specified assessment measures. It was expected that the confounding factors would be reported and controlled for and appropriate data analysis made in addition to an explanation of missing data.

Data synthesis

A structured, systematic review was performed with the results tabulated.

Results

In total, 38 potentially relevant publications were identified. A total of four studies were included in the review as they were deemed eligible by fulfilling the inclusion criteria. These studies examined the role of autophagy-related gene 7 in the pathogenesis of vitiligo. The studies were analyzed with respect to the study design using the classification of the US Preventive Services Task Force and UK National Health Service protocol for EBM.

The role of ATG7 in the pathogenesis of vitiligo according to evidence base medicine was investigated in three studies ([Table 1] and [Table 2]) which were case–control studies that falls under level II EBM, review article under level I, and animal studies that comes in the base of the EBM pyramid . Dysregulated autophagy or suppression of it causes premature senescence of MCs and increased MC sensitivity to oxidative stress [7],[10]. Qiao et al. [8] indicated that the disturbance of autophagy of MCs may be the mechanism of vitiligo pathogenesis. Another review described the pleiotropic roles of autophagy regulators in multiple vesicle trafficking processes, define a specific role for autophagy regulators in melanosome biogenesis, and shed light on how autophagy and autophagy regulators may play different roles in both the biogenesis of melanosomes and melanosome destruction [9]. He and colleagues demonstrated that dysregulated autophagy owing to the impairment of Nrf2-p62 pathway increases the sensitivity of vitiligo MCs to oxidative stress, thus promoting the development of vitiligo. Upregulation of p62-dependent autophagy may be applied to vitiligo treatment in the future [10].

Table 1 Studies investigating the role of ATG7 and autophagy in vitiligo

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Table 2 Level of evidence of studies investigating the role of ATG7 and autophagy in vitiligo

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Discussion

Vitiligo is an acquired disease clinically characterized by well-defined depigmented macules or patches that may occur due to MC dysfunction and loss. It has a variable course. It is the most common depigmentation disorder, has no predilection for sex or race [2]. Zhang and colleagues study using ATG7-floxed mice and TyrCre mice to determine the contribution of autophagy to MC biology; they inactivated the essential autophagy gene ATG7 specifically in MCs using the Cre-loxP system. Autophagy-related gene 7-deficient MCs entered into premature growth arrest and accumulated reactive oxygen species damage, ubiquitinated proteins, and the multifunctional adapter protein SQSTM1/p62. Moreover, nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent expression of NAD(P)H dehydrogenase, quinone 1, and glutathione S-transferase Mu 1 was increased, indicating a contribution of autophagy to redox homeostasis in MCs. In summary, the results of our study suggest that autophagy-related gene 7-dependent autophagy is dispensable for melanogenesis but necessary for achieving the full proliferative capacity of MCs [7].

Impairment of autophagy might disrupt the antioxidant defense system which renders MCs to oxidative insults. These findings provide supportive evidence to explore new ideas of the pathogenesis of vitiligo and other pigmentation disorders [8]. Recent functional genomic studies have identified a role for genes previously known to regulate autophagy, a cellular process that facilitates nutrient recycling during starvation, in the biogenesis of melanosomes in vitro and in vivo. In this review, we describe the pleiotropic roles of autophagy regulators in multiple vesicle trafficking processes, define a specific role for autophagy regulators in melanosome biogenesis, and shed light on how autophagy and autophagy regulators may play different roles in both the biogenesis of melanosomes and melanosome destruction [9]. In addition, dysregulated autophagy increased MC sensitivity to H₂O₂-induced oxidative stress in vitiligo [10].

Burgoyne show that oxidative stress impairs autophagy through the oxidation of ATG3 and ATG7. When autophagy is inactive, ATG3 and ATG7 form a stable thioester with LC3 that becomes transient upon stimulation of the autophagy pathway. Transient interaction of ATG3 and ATG7 with LC3 exposes catalytic thiols, which in the presence of reactive oxygen species undergo oxidation to form a disulfide heterodimer or a glutathione adduct. The oxidation of catalytic thiols on ATG3 and ATG7 prevents the interaction with, and lipidation of, LC3 required for functional autophagy [2]. Last but not least, we recommended that more studies are needed to show the role of autophagy in vitiligo (segmental and nonsegmental) and its interplay with oxidative stress [11].

Conclusion

Autophagy with its marker autophagy-related gene 7 (ATG7) plays an important role in the pathogenesis of vitiligo through its effect on melanogenesis and MC premature senescence.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Czajkowski R, Męcinska-Jundziłł K. Current aspects of vitiligo genetics. Dermatol Allergol 2014; 31:247–255.
2.	Ezzedine K, Eleftheriadou V, Whitton M, van Geel N. Vitiligo. Lancet 2015; 386:74–84.
3.	Zhang Z, Xu SX, Zhang FY, Yin XY, Yang S, Xiao FL et al. The analysis of genetics and associated autoimmune diseases in Chinese vitiligo patients. Arch Dermatol Res 2009; 301:167–173.
4.	Yang Z, Klionsky DJ. Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol 2010; 22:124–131.
5.	Feng Y, Yao Z, Klionsky DJ. How to control self-digestion: transcriptional, post-transcriptional, and post-translational regulation of autophagy. Trends Cell Biol 2015; 25:354–363.
6.	Nakatogawa H, Ichimura Y, Ohsumi Y. Atg8, a ubiquitin-like protein required for autophagosome formation, mediates membrane tethering and hemifusion. Cell 2007; 130:165–178.
7.	Zhang C-F., Gruber F, Ni C, Mildner M, Koenig U, Karner S et al. Suppression of autophagy dysregulates the antioxidant response and causes premature senescence of melanocytes. J Invest Dermatol 2015; 135:1348–1357.
8.	Qiao Z, Wang X, Xiang L, Zhang C. Dysfunction of autophagy: a possible mechanism involved in the pathogenesis of vitiligo by breaking the redox balance of melanocytes. Oxid Med Cell Longev 2016; 7:3401570.
9.	Ho H, Ganesan AK. The pleiotropic role of autophagy regulation in melanogenesis. Pigment Cell Melanoma Res 2011; 24:595–604.
10.	He Y, Li S, Zhang W, Dai W, Cui T, Wang G et al. Dysregulated autophagy increased melanocyte sensitivity to H2O2-induced oxidative stress in vitiligo. Sci Rep 2017; 7:42394.
11.	Burgoyne JR. Oxidative stress impairs autophagy through oxidation of ATG3 and ATG7. Autophagy 2018; 14:1092–1093.