Loss of RhoE function in dermatofibroma promotes disorganized dermal fibroblast extracellular matrix and increased integrin activation

Sofia Endzhievskaya; Chao-Kai Hsu; Hsing-San Yang; Hsin-Yu Huang; Yu-Chen Lin; John Y W Lee; Alexandros Onoufriadis; Takuya Takeichi; Julia Yu-Yun Lee; Tanya Shaw; John McGrath; Madeline Parsons

doi:10.1016/j.jid.2023.01.019

Loss of RhoE function in dermatofibroma promotes disorganized dermal fibroblast extracellular matrix and increased integrin activation

Sofia Endzhievskaya, Chao-Kai Hsu, Hsing-San Yang, Hsin-Yu Huang, Yu-Chen Lin, John Y W Lee, Alexandros Onoufriadis, Takuya Takeichi, Julia Yu-Yun Lee, Tanya Shaw, John McGrath, Madeline Parsons^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

2 Citations (Scopus)

Abstract

Dermatofibromas (DFs) are common, benign fibrous skin tumors that can occur at any skin site. In most cases, DFs are solitary and sporadic, but a few are multiple and familial, and the mechanisms leading to these lesions are currently unclear. Using exome sequencing, we have identified a heterozygous variant in a pedigree with autosomal dominant multiple familial DF within RND3 (c.692C>T,p.T231M) that encodes for the small GTPase RhoE, a regulator of the actin cytoskeleton. Expression of T231M-RhoE or RhoE depletion using CRISPR in human dermal fibroblasts increased proliferation and adhesion to extracellular matrix through enhanced β1 integrin activation and more disorganized matrix. The enzyme PLOD2 was identified as a binding partner for RhoE, and the formation of this complex was disrupted by T231M-RhoE. PLOD2 promotes collagen cross-linking and activation of β1 integrins, and depleting PLOD2 in T231M-RhoE–expressing cells reduced T231M-RhoE–mediated β1 integrin activation and led to increased matrix alignment. Immunohistochemical analysis revealed reduced expression of RhoE but increased expression of PLOD2 in the dermis of DF skin samples compared with that of the controls. Our data show that loss of RhoE function leads to increased PLOD2 activation, enhancing integrin activation and leading to a disorganized extracellular matrix, contributing to DF.

Original language	English
Pages (from-to)	1487-1497.e9
Journal	Journal of Investigative Dermatology
Volume	143
Issue number	8
DOIs	https://doi.org/10.1016/j.jid.2023.01.019
Publication status	Published - 10 Feb 2023

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Endzhievskaya, S., Hsu, C.-K., Yang, H.-S., Huang, H.-Y., Lin, Y.-C., Lee, J. Y. W., Onoufriadis, A., Takeichi, T., Lee, J. Y.-Y., Shaw, T., McGrath, J., & Parsons, M. (2023). Loss of RhoE function in dermatofibroma promotes disorganized dermal fibroblast extracellular matrix and increased integrin activation. Journal of Investigative Dermatology, 143(8), 1487-1497.e9. https://doi.org/10.1016/j.jid.2023.01.019

@article{c89a4819213f46c483c9b50bda0158b6,

title = "Loss of RhoE function in dermatofibroma promotes disorganized dermal fibroblast extracellular matrix and increased integrin activation",

abstract = "Dermatofibromas (DFs) are common, benign fibrous skin tumors that can occur at any skin site. In most cases, DFs are solitary and sporadic, but a few are multiple and familial, and the mechanisms leading to these lesions are currently unclear. Using exome sequencing, we have identified a heterozygous variant in a pedigree with autosomal dominant multiple familial DF within RND3 (c.692C>T,p.T231M) that encodes for the small GTPase RhoE, a regulator of the actin cytoskeleton. Expression of T231M-RhoE or RhoE depletion using CRISPR in human dermal fibroblasts increased proliferation and adhesion to extracellular matrix through enhanced β1 integrin activation and more disorganized matrix. The enzyme PLOD2 was identified as a binding partner for RhoE, and the formation of this complex was disrupted by T231M-RhoE. PLOD2 promotes collagen cross-linking and activation of β1 integrins, and depleting PLOD2 in T231M-RhoE–expressing cells reduced T231M-RhoE–mediated β1 integrin activation and led to increased matrix alignment. Immunohistochemical analysis revealed reduced expression of RhoE but increased expression of PLOD2 in the dermis of DF skin samples compared with that of the controls. Our data show that loss of RhoE function leads to increased PLOD2 activation, enhancing integrin activation and leading to a disorganized extracellular matrix, contributing to DF.",

author = "Sofia Endzhievskaya and Chao-Kai Hsu and Hsing-San Yang and Hsin-Yu Huang and Yu-Chen Lin and Lee, {John Y W} and Alexandros Onoufriadis and Takuya Takeichi and Lee, {Julia Yu-Yun} and Tanya Shaw and John McGrath and Madeline Parsons",

note = "Funding Information: This research was funded/supported by the National Institute for Health and Care Research Biomedical Research Centre based at Guy's and St Thomas{\textquoteright} NHS Foundation Trust and King's College London and/or the National Institute for Health and Care Research Clinical Research Facility. We thank Dhylan Patel (King's College London) for assistance with migration data analysis, Ritu Garg (King's College London) for providing advice and TAOK inhibitor, Eisaku Kondo (Niigata University, Japan) for providing PLOD2 constructs, Steve Lynham (King's College London Proteomics Core facility) for assistance with mass spec, and Debbie Finch (King's College London Comprehensive Cancer Centre) for assistance with tissue slide scanning. Conceptualization: MP, JAM; Formal Analysis: SE, MP, CKH, HSY, HYH, JYWL, TT, JYYL; Funding Acquisition: MP, JAM, AO, CKH; Investigation: SE, CKH, HSY, HYH, YCL, YKH, JYWL, TT, JYYL; Methodology: SE, TS, MP; Resources: MP, CKH, JYYL; Supervision: MP, TS; Writing - Original Draft Preparation: MP, SE; Writing - Review and Editing: SE, CKH, TS, JAM, JYYL, The views expressed are those of the authors and not necessarily those of the NHS, the National Institute for Health and Care Research, or the Department of Health and Social Care. Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = feb,

day = "10",

doi = "10.1016/j.jid.2023.01.019",

language = "English",

volume = "143",

pages = "1487--1497.e9",

journal = "Journal of Investigative Dermatology",

issn = "0022-202X",

publisher = "Nature Publishing Group",

number = "8",

}

Endzhievskaya, S, Hsu, C-K, Yang, H-S, Huang, H-Y, Lin, Y-C, Lee, JYW, Onoufriadis, A, Takeichi, T, Lee, JY-Y, Shaw, T , McGrath, J & Parsons, M 2023, 'Loss of RhoE function in dermatofibroma promotes disorganized dermal fibroblast extracellular matrix and increased integrin activation', Journal of Investigative Dermatology, vol. 143, no. 8, pp. 1487-1497.e9. https://doi.org/10.1016/j.jid.2023.01.019

TY - JOUR

T1 - Loss of RhoE function in dermatofibroma promotes disorganized dermal fibroblast extracellular matrix and increased integrin activation

AU - Endzhievskaya, Sofia

AU - Hsu, Chao-Kai

AU - Yang, Hsing-San

AU - Huang, Hsin-Yu

AU - Lin, Yu-Chen

AU - Lee, John Y W

AU - Onoufriadis, Alexandros

AU - Takeichi, Takuya

AU - Lee, Julia Yu-Yun

AU - Shaw, Tanya

AU - McGrath, John

AU - Parsons, Madeline

N1 - Funding Information: This research was funded/supported by the National Institute for Health and Care Research Biomedical Research Centre based at Guy's and St Thomas’ NHS Foundation Trust and King's College London and/or the National Institute for Health and Care Research Clinical Research Facility. We thank Dhylan Patel (King's College London) for assistance with migration data analysis, Ritu Garg (King's College London) for providing advice and TAOK inhibitor, Eisaku Kondo (Niigata University, Japan) for providing PLOD2 constructs, Steve Lynham (King's College London Proteomics Core facility) for assistance with mass spec, and Debbie Finch (King's College London Comprehensive Cancer Centre) for assistance with tissue slide scanning. Conceptualization: MP, JAM; Formal Analysis: SE, MP, CKH, HSY, HYH, JYWL, TT, JYYL; Funding Acquisition: MP, JAM, AO, CKH; Investigation: SE, CKH, HSY, HYH, YCL, YKH, JYWL, TT, JYYL; Methodology: SE, TS, MP; Resources: MP, CKH, JYYL; Supervision: MP, TS; Writing - Original Draft Preparation: MP, SE; Writing - Review and Editing: SE, CKH, TS, JAM, JYYL, The views expressed are those of the authors and not necessarily those of the NHS, the National Institute for Health and Care Research, or the Department of Health and Social Care. Publisher Copyright: © 2023 The Authors

PY - 2023/2/10

Y1 - 2023/2/10

N2 - Dermatofibromas (DFs) are common, benign fibrous skin tumors that can occur at any skin site. In most cases, DFs are solitary and sporadic, but a few are multiple and familial, and the mechanisms leading to these lesions are currently unclear. Using exome sequencing, we have identified a heterozygous variant in a pedigree with autosomal dominant multiple familial DF within RND3 (c.692C>T,p.T231M) that encodes for the small GTPase RhoE, a regulator of the actin cytoskeleton. Expression of T231M-RhoE or RhoE depletion using CRISPR in human dermal fibroblasts increased proliferation and adhesion to extracellular matrix through enhanced β1 integrin activation and more disorganized matrix. The enzyme PLOD2 was identified as a binding partner for RhoE, and the formation of this complex was disrupted by T231M-RhoE. PLOD2 promotes collagen cross-linking and activation of β1 integrins, and depleting PLOD2 in T231M-RhoE–expressing cells reduced T231M-RhoE–mediated β1 integrin activation and led to increased matrix alignment. Immunohistochemical analysis revealed reduced expression of RhoE but increased expression of PLOD2 in the dermis of DF skin samples compared with that of the controls. Our data show that loss of RhoE function leads to increased PLOD2 activation, enhancing integrin activation and leading to a disorganized extracellular matrix, contributing to DF.

AB - Dermatofibromas (DFs) are common, benign fibrous skin tumors that can occur at any skin site. In most cases, DFs are solitary and sporadic, but a few are multiple and familial, and the mechanisms leading to these lesions are currently unclear. Using exome sequencing, we have identified a heterozygous variant in a pedigree with autosomal dominant multiple familial DF within RND3 (c.692C>T,p.T231M) that encodes for the small GTPase RhoE, a regulator of the actin cytoskeleton. Expression of T231M-RhoE or RhoE depletion using CRISPR in human dermal fibroblasts increased proliferation and adhesion to extracellular matrix through enhanced β1 integrin activation and more disorganized matrix. The enzyme PLOD2 was identified as a binding partner for RhoE, and the formation of this complex was disrupted by T231M-RhoE. PLOD2 promotes collagen cross-linking and activation of β1 integrins, and depleting PLOD2 in T231M-RhoE–expressing cells reduced T231M-RhoE–mediated β1 integrin activation and led to increased matrix alignment. Immunohistochemical analysis revealed reduced expression of RhoE but increased expression of PLOD2 in the dermis of DF skin samples compared with that of the controls. Our data show that loss of RhoE function leads to increased PLOD2 activation, enhancing integrin activation and leading to a disorganized extracellular matrix, contributing to DF.

UR - http://www.scopus.com/inward/record.url?scp=85150245203&partnerID=8YFLogxK

U2 - 10.1016/j.jid.2023.01.019

DO - 10.1016/j.jid.2023.01.019

M3 - Article

SN - 0022-202X

VL - 143

SP - 1487-1497.e9

JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

IS - 8

ER -

Loss of RhoE function in dermatofibroma promotes disorganized dermal fibroblast extracellular matrix and increased integrin activation

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