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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 31  |  Issue : 3  |  Page : 822-825

Role of beclin 1 and autophagy in vitiligo


1 Department of Pathology, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt
2 Department of Dermatology and Andrology, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt
3 Department of Dermatology, Menouf Hospital, Menouf, Menoufia Governorate, Egypt

Date of Submission20-Feb-2018
Date of Acceptance10-Apr-2018
Date of Web Publication31-Dec-2018

Correspondence Address:
Amany M Zahran
Department of Dermatology, Menouf Hospital, Menouf 32951, Menoufia Governorate
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_88_18

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  Abstract 


Objective
The objective of this study was to perform a systematic review to summarize the role of beclin 1 and autophagy in vitiligo.
Background
Vitiligo is an acquired autoimmune pigmentary disorder due to loss of functional melanocytes. Few studies have shown that beclin 1 and autophagy play a role in vitiligo.
Materials and methods
Medline databases (PubMed, Medscape, ScienceDirect) and all materials published in English language are available on the Internet from 2008 to 2017. The search was performed in December 2017. 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, and focused on the role of beclin 1 in vitiligo. The initial search presented 16 articles of which three met the inclusion criteria. The articles studied the effect of role of beclin 1 in vitiligo. If the studies did not fulfill the above criteria, they were excluded. Comparisons were made by a structured review with the results tabulated.
Results
In total, three potentially relevant publications were included; there was an association between vitiligo, autophagy, and beclin 1. This association was due to the effect of beclin 1 as an autophagy gene on melanogenesis and melanosome degradation.
Conclusion
Beclin1 and autophagy have a role in the pathogenesis of vitiligo.

Keywords: autophagy, beclin 1, skin, vitiligo


How to cite this article:
Samaka RM, Basha MA, Zahran AM. Role of beclin 1 and autophagy in vitiligo. Menoufia Med J 2018;31:822-5

How to cite this URL:
Samaka RM, Basha MA, Zahran AM. Role of beclin 1 and autophagy in vitiligo. Menoufia Med J [serial online] 2018 [cited 2019 Jan 22];31:822-5. Available from: http://www.mmj.eg.net/text.asp?2018/31/3/822/248769




  Introduction Top


Vitiligo is the commonest depigmentation skin disease with an estimated prevalence of 1% of the population worldwide. The disease seems to affect all skin types and ethnic groups equally[1]. Vitiligo is an acquired cutaneous disorder characterized by progressive, selective destruction of melanocytes leading to the development of milky white macules and patches[2].

It is a multifactorial polygenic disorder and several theories have been proposed about the pathogenesis of vitiligo including autoimmune hypothesis, reactive oxygen species (ROS) model, zinc-α2-glycoprotein deficiency hypothesis, viral theory, intrinsic theory, and biochemical, molecular, and cellular alterations accounting for loss of functioning melanocytes[3]. Vitiligo can be clinically classified as generalized vitiligo that includes acrofacial, vulgaris, universalis, and mixed forms. Localized vitiligo can affect one, two, or multiple segments and includes focal, segmental, and mucosal forms. There are also mixed and undetermined forms of vitiligo[3],[4]. Autophagy is the central cellular mechanism for delivering organelles and cytoplasm to lysosomes for degradation and recycling of their molecular components. Defects in autophagy have implications for melanocyte survival and manifestations of skin pigmentary disorders. It has been shown that melanocytes lacking the autophagy proteins undergo premature senescence in vitro and accumulate products of oxidative damage leading to pigment dilution[5]. Autophagy contributes to maintain intercellular homeostasis[6].

A number of putative regulators of autophagy were identified as potent regulators of melanogenesis[7]. Autophagy clearly plays important roles in most of the major human diseases as defects in autophagy have been implicated in manifestations of skin pigmentary disorders such as vitiligo[8].

Immunohistochemical studies have determined that beclin 1 is expressed in melanocytic lesions[9]. Expression of beclin 1 was elevated in melanocytic nevi, as detected by immunohistochemical staining and immunofluorescence analysis in the nests of pigmented nevi of sun-exposed skin but not in the basal layer of normal skin[10]. Beclin 1 have recently been identified in mammalian cells as two complexes: one complex, considered the equivalent of the yeast complex I that is essential for autophagy, includes a human ortholog of yeast Atg14 that is required for autophagy. The other complex, considered the equivalent of the yeast complex II, that functions in the vacuolar protein sorting pathway, includes ultraviolet irradiation resistance-associated gene (UVRAG), which is proposed to be the human ortholog of yeast, Vps38[11]. The UVRAG -containing beclin 1/class III phosphoinositide-3 kinase complex is not required for autophagosome formation; these findings contradict an earlier report that UVRAG is required for autophagy[12]. Further, Bif-1, which binds to UVRAG and regulates membrane curvature[13], and the activating molecule in beclin 1-regulated autophagy, which binds to beclin 1 in a complex containing UVRAG[14], have each been shown to upregulate the autophagy function of the beclin 1/class III phosphoinositide-3 kinase complex.

This study aimed to review the literature for the assessment of the role of beclin 1 and autophagy in vitiligo.


  Materials and Methods Top


Search strategy

We reviewed papers on the relation between vitiligo, autophagy, and beclin 1 from Medline databases which are PubMed, Medscape, ScienceDirect and also materials available in the Internet from 2008 to 2017. We used skin, vitiligo, autophagy, and beclin1 as the search terms.

Study selection

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

  1. Inclusion criteria of the published studies
  2. Explain autophagy as a mechanism of vitiligo
  3. Beclin 1 assay in vitiligo by any technique
  4. Published in English language
  5. Published in peer-reviewed journals.


Data extraction

If the studies did not fulfill the inclusion criteria, they were excluded such as studies on beclin 1 in systemic diseases or skin diseases other than vitiligo, report without peer review, not within the national research program, letters/comments/editorials/news.

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:

  1. Level I: evidence obtained from at least one properly designed randomized, controlled trial
  2. Level II-1: evidence obtained from well-designed controlled trails without randomization
  3. Level II-2: evidence obtained from well-designed cohort or case–control analytic studies preferably from more than one center or research group
  4. 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
  5. 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 study design, attainment of ethical approval, evidence of a 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 Top


In total, 16 potentially relevant publications were identified; 13 articles were excluded as they did not meet our inclusion criteria. A total of three studies were included in the review as they were deemed eligible by fulfilling the inclusion criteria and relevant to the aim of the study. From these studies, only three studies were intensely related to our aims. These studies examined the role of beclin 1 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 beclin 1 in the pathogenesis of vitiligo according to evidence base medicine was investigated in three studies [Table 1] and [Table 2] that were the case–control study which comes in level II EBM; review article which comes in level I; animal study that comes in the base of the EBM pyramid. Qiao et al.[15] indicated that oxidative stress plays an important role in initiating the destruction of melanocytes and impairment of redox balance could be one possible mechanism of vitiligo. As autophagy possesses a protective and restorative function to the damage induced by oxidative stress, deficiency of autophagy might lead to alteration of cell functions such as proliferation, senescence, and ROS scavenging[15]. Ganesan et al.[7] have shown that heterozygous deletion of the autophagy protein beclin 1 in mice results in a lighter coat color. Mouse skin sections from four wild-type and four beclin 1 haploinsufficient mice were fixed in formalin and were paraffin embedded. Hematoxylin and eosin staining were performed following standard protocols. Melanin was stained using the Fontana-Masson technique with a neutral red counterstain. S100 staining was performed as described using an eosin counterstain[7]. In the study presented by Gong et al.[16], they treated human melanocytes with 0.05% H2O2 as well as various concentrations of calcipotriol and found that the expression of beclin 1 was higher in the calcipotriol-treated melanocytes than in the control or H2O2-treated melanocytes.
Table 1: Studies investigating the role of beclin 1 and autophagy in vitiligo

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Table 2: Studies investigating the role of beclin 1 and autophagy in vitiligo

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  Discussion Top


Vitiligo is a common, chronic acquired pigmentation disorder characterized by loss of functional melanocytes from the epidermis and follicular reservoir[15]. The exact pathogenesis of vitiligo remains unknown but the number of mechanisms such as oxidative stress, autoimmune, autocytotoxicity, genetic factors, neural, and melanocytorrhagy have been proposed for the pathogenesis of vitiligo[15]. There was a functional relationship between autophagosome and melanosome biogenesis. Furthermore, the depletion of an additional component required to trigger autophagosome formation, beclin 1, severely impaired pigment accumulation[7].

Although the mechanism of melanocyte loss in vitiligo has not yet been clarified, a rising number of studies provided evidence that dysfunction of autophagy may serve as a vital factor through possible associations between autophagy and melanosome biogenesis, formation, and destruction by members of the autophagic machinery. However, direct evidence for this claim is still lacking. Autophagy may be involved in determining the skin color by regulating melanosome degradation in keratinocytes, so that autophagy has implications for melanocyte dysfunction and manifestations of skin pigmentary disorders[15]. Oxidative stress plays an important role in initiating the destruction of melanocytes and impairment of redox balance could be one possible mechanism of vitiligo. As autophagy possesses a protective and restorative function to the damage induced by oxidative stress, deficiency of autophagy might lead to alteration of cell functions such as proliferation, senescence, and ROS scavenging. On the basis of the similarity between Atg7-deficient and vitiligo phenotypes, specifically with respect to the activation of Nrf2-regulated genes, oxidative stress, and premature senescence, it is very likely that autophagy-deficient melanocytes and vitiligo melanocytes share defective cellular redox regulation, increased membrane lipid oxidation, and premature senescence[17].

To evaluate the role of autophagy on oxidative stress, Gong et al.[16] introduced antioxidant calcipotriol to human melanocytes compared with H2O2-treated melanocytes. Their results demonstrate the antioxidant effect of calcipotriol on human melanocytes subjected to oxidative damage by the activation of autophagy as calcipotriol-treated melanocytes had a higher beclin 1 expression compared with H2O2-treated melanocytes, suggesting an increased activation of autophagy. Observation by transmission electron microscopy suggested that calcipotriol might reduce the injury of mitochondria in melanocytes under oxidative stress. Furthermore, the expression of beclin 1 was higher in the calcipotriol-treated melanocytes than in the control or H2O2-treated melanocytes. Moreover, calcipotriol could be a promising drug delivery strategy to protect melanocytes against oxidative damage in vitiligo through autophagy or mitophagy[16].


  Conclusion Top


Autophagy and beclin 1 play an important role in the pathogenesis of vitiligo through its effect on melanogenesis and melanosome degradation in keratinocytes.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Ezzedine K, Eleftheriadou V, Whitton M, van Geel N. Vitiligo. Lancet 2015; 386:74–84.  Back to cited text no. 1
    
2.
Alikhan A, Felsten LM, Daly M, Petronic-Rosic V. Vitiligo: a comprehensive overview. Part I. Introduction, epidemiology, quality of life, diagnosis, differential diagnosis, associations, histopathology, etiology, and work-up. J Am Acad Dermatol 2011; 65:473–491.  Back to cited text no. 2
    
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Mohammed GF, Gomaa AH, Al-Dhubaibi MS. Highlights in pathogenesis of vitiligo. World J Clin Cases 2015; 3:221–230.  Back to cited text no. 3
    
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7.
Ganesan AK, Ho H, Bodemann B, Petersen S, Aruri J, Kashy S. Genome-wide siRNA-based functional genomics of pigmentation identifies novel genes and pathways that impact melanogenesis in human cells. PLoS Genet 2008; 4:e1000298.  Back to cited text no. 7
    
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Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell 2008; 132:27–42.  Back to cited text no. 8
    
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Miracco C, Cevenini G, Franchi A, Luzi P, Cosci E, Mourmouras V, et al. Beclin 1 and LC3 autophagic gene expression in cutaneous melanocytic lesions. Hum Pathol 2010; 41:503–512.  Back to cited text no. 9
    
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Yun WJ, Kim EY, Park JE, Jo SY, Bang SH, Chang EJ, et al. Microtubule-associated protein light chain 3 is involved in melanogenesis via regulation of MITF expression in melanocytes. Sci Rep 2016; 6:19914.  Back to cited text no. 10
    
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Itakura E, Kishi C, Inoue K, Mizushima N. Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Mol Biol Cell 2008; 19:5360–5372.  Back to cited text no. 11
    
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Liang C, Feng P, Ku B, Oh BH, Jung JU. UVRAG: a new player in autophagy and tumor cell growth. Autophagy 2007; 3:69–71.  Back to cited text no. 12
    
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Takahashi Y, Coppola D, Matsushita N, Cualing H, Sun M, Sato Y, et al. Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat Cell Biol 2007; 9:1142–1151.  Back to cited text no. 13
    
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Fimia G, Stoykova A, Romagnoli A, Giunta L, Bartolomeo SD, Nardacci R, et al. Ambra1 regulates autophagy and development of the nervous system. Nature 2007; 447:1121–1125.  Back to cited text no. 14
    
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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; 2016:3401570.  Back to cited text no. 15
    
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Gong Q, Li X, Sun J, Ding G, Zhou M, Zhao W, et al. The effects of calcipotriol on the dendritic morphology of human melanocytes under oxidative stress and a possible mechanism: is it a mitochondrial protector? J Dermatol Sci 2015; 77:117–124.  Back to cited text no. 16
    
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Setaluri V. Autophagy as a melanocytic self-defense mechanism. J Invest Dermatol 2015; 135:1215–1217.  Back to cited text no. 17
    



 
 
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