RAB25 coordinates filaggrin‐containing keratohyalin granule maturation and affects atopic dermatitis severity. Issue 4 (21st November 2022)

• Record Type: Journal Article
• Authors: Jeong, Haengdueng; Lee, Nakyum; Uhm, Chanyang; Cho, Kyungrae; Oh, Heeju; Oh, Yeseul; Zhang, KeLun; Kim, Hye Li; Goldenring, James R.; Lim, Kyung‐Min; Park, Chang Ook; Nam, Ki Taek
• Is Part Of: Allergy. Volume 78:Issue 4(2023)
• Page Start: 1007
• Page End: 1019
• Publication Date: 2022-11-21
• Subjects: atopic dermatitis -- Filaggrin -- Keratohyalin granule -- RAB25; Allergy -- Periodicals; 616.97
• DOI: 10.1111/all.15582
• Languages: English
• ISSNs: 0105-4538

Abstract

Abstract: Background: Keratohyalin granules (KHGs) supply the critical epidermal protein constituents such as filaggrin for maintaining skin barrier function during epidermal differentiation; however, their regulating mechanism remains largely unelucidated. Methods: To investigate the role of Ras‐related protein Rab‐25 (RAB25) expression in skin disease, we utilized skin specimens of patients with moderate‐to‐severe atopic dermatitis (AD) and healthy controls. To investigate the susceptibility of Rab25 knockout mice to AD, we established an oxazolone‐induced AD model. Results: We investigated the role of RAB25 in KHG maturation and AD. RAB25‐deficient mice showed a disrupted stratum corneum along with skin barrier dysfunction, decreased KHG production, and abnormal KHG processing. Consistently, in the human keratinocyte cell line HaCaT, RAB25 co‐expressed with filaggrin‐containing KHG and RAB25 silencing impaired KHG formation, which was attributable to abnormal actin dynamics. Most importantly, RAB25 expression was severely downregulated in the skin lesions of patients with AD, which was strongly correlated with disease severity scores. Conclusions: RAB25 coordinates KHG homeostasis by regulating actin dynamics and is critical for epidermal differentiation and the pathophysiology of AD. Abstract : RAB25 is downregulated in AD patients and is correlates with the severity of AD. Rab25 KO mice are more susceptible to oxazolone‐induced AD compared to WT mice, but recovery of actin dynamics in Rab25 KO mice ameliorates AD severity. RAB25 modulates FLG‐containing KHG maturation by regulating actin dynamics in skin, but defect in RAB25 expression impairs KHG maturation, leading to aberrant FLG expression.Abbreviations: AD, atopic dermatitis; IgE, immunoglobulin E; KHG, Keratohyalin granule; KO, Knockout; RAB25, Ras‐related protein 25; WT, wild type