Comparative ubiquitinomics of human skin reveals insulin receptor ubiquitination as a regulator of collagen secretion
Abstract
Ubiquitination is central to skin homoeostasis, however the cutaneous ubiquitinome remains poorly characterised. We investigated ubiquitination architecture in human skin, discovering ubiquitin linkage type localisation of within the hair follicle and epidermis. We profiled healthy skin through di-glycine remnant immunopurification proteomics, identifying 1465 sites across histone, S100 and keratin protein classes. Predictive upstream enzyme analysis ranked the most frequent E3 ligases and deubiquitinases as NEDD4, USP7 and CYLD. Analysis of CCS tumours, characterised by catalytically inactivated CYLD somatic mutations and prominent extracellular matrix (ECM) secretion, identified 251 differentially ubiquitinated sites compared to healthy skin. The CCS ubiquitinome was enriched for cell division and differentiation proteins, including predicted CYLD substrate insulin receptor (INSR). Secretome analysis of INSR knockdown CCS primary cells revealed reduced secretion of basement membrane proteins, particularly COL7A1. By defining how ubiquitination modulates pathophysiological ECM secretion, our study highlights the ubiquitin system as a broader determinant of tissue architecture.
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BibTeX
@article{inns2026comparative,
title = {{Comparative ubiquitinomics of human skin reveals insulin receptor ubiquitination as a regulator of collagen secretion}},
author = {Joseph Inns and Andrew Michael Frey and Ishier Raote and Hong Ha Nguyen and Mads Gyrd-Hansen and Matthias Trost and Neil Rajan},
journal = {Communications Biology},
year = {2026},
month = sep,
doi = {10.1038/s42003-026-10930-5},
url = {https://hal.science/hal-05784617v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Comparative ubiquitinomics of human skin reveals insulin receptor ubiquitination as a regulator of collagen secretion
AU - Joseph Inns
AU - Andrew Michael Frey
AU - Ishier Raote
AU - Hong Ha Nguyen
AU - Mads Gyrd-Hansen
AU - Matthias Trost
AU - Neil Rajan
PY - 2026
DA - 2026/09/17
JO - Communications Biology
DO - 10.1038/s42003-026-10930-5
UR - https://hal.science/hal-05784617v1
AB - Ubiquitination is central to skin homoeostasis, however the cutaneous ubiquitinome remains poorly characterised. We investigated ubiquitination architecture in human skin, discovering ubiquitin linkage type localisation of within the hair follicle and epidermis. We profiled healthy skin through di-glycine remnant immunopurification proteomics, identifying 1465 sites across histone, S100 and keratin protein classes. Predictive upstream enzyme analysis ranked the most frequent E3 ligases and deubiquitinases as NEDD4, USP7 and CYLD. Analysis of CCS tumours, characterised by catalytically inactivated CYLD somatic mutations and prominent extracellular matrix (ECM) secretion, identified 251 differentially ubiquitinated sites compared to healthy skin. The CCS ubiquitinome was enriched for cell division and differentiation proteins, including predicted CYLD substrate insulin receptor (INSR). Secretome analysis of INSR knockdown CCS primary cells revealed reduced secretion of basement membrane proteins, particularly COL7A1. By defining how ubiquitination modulates pathophysiological ECM secretion, our study highlights the ubiquitin system as a broader determinant of tissue architecture.
SN - 2399-3642
ER -