A Novel Regulatory Role for RPS4Y1 in Inflammatory and Fibrotic Processes

Asthma is a chronic inflammatory respiratory disease well-known to demonstrate sexual dimorphism in incidence and severity, although the mechanisms causing these differences remain incompletely understood. RPS4X and RPS4Y1 are X and Y-chromosome-linked genes coding ribosomal subunits previously asso...

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Bibliographic Details
Published in:International journal of molecular sciences Vol. 26; no. 13; p. 6213
Main Authors: Reddy, Karosham D., Rathnayake, Senani N. H., Idrees, Sobia, Boedijono, Fia, Xenaki, Dikaia, Padula, Matthew P., Berge, Maarten van den, Faiz, Alen, Oliver, Brian G. G.
Format: Journal Article
Language:English
Published: Switzerland MDPI AG 01.07.2025
Subjects:
Amino acids
Analysis
Animals
Asthma
Asthma - genetics
Asthma - metabolism
Asthma - pathology
Cell cycle
Cell growth
CRISPR-Cas Systems
Cytokines
Disease
Enzymes
Extracellular matrix
Female
Females
Fibrosis
Gene expression
Genes
Genetic aspects
Genetic translation
Genomes
Humans
Inflammation
Inflammation - genetics
Inflammation - metabolism
Inflammation - pathology
Interleukin-6 - genetics
Interleukin-6 - metabolism
Male
Males
Medical prognosis
Medical research
Medicine, Experimental
Proteins
Respiratory agents
Ribonucleic acid
Ribosomal Proteins - genetics
Ribosomal Proteins - metabolism
RNA
Tenascin - genetics
Tenascin - metabolism
X chromosomes
Y chromosomes
United States
Massachusetts
Germany
RNA-seq
inflammation
CRISPR-Cas9
Y-chromosome
asthma
fibrosis
sex differences
ISSN:1422-0067, 1661-6596, 1422-0067
Online Access:Get full text
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Summary:Asthma is a chronic inflammatory respiratory disease well-known to demonstrate sexual dimorphism in incidence and severity, although the mechanisms causing these differences remain incompletely understood. RPS4X and RPS4Y1 are X and Y-chromosome-linked genes coding ribosomal subunits previously associated with inflammation, airway remodelling and asthma medication efficacy. Particularly, RPS4Y1 has been under-investigated within the context of disease, with little examination of molecular mechanisms and pathways regulated by this gene. The ribosome, a vital cellular machinery, facilitates the translation of mRNA into peptides and then proteins. Imbalance or dysfunction in ribosomal components may lead to malfunctioning proteins. Using CRISPR-Cas9 knockout cellular models for RPS4Y1 and RPS4X, we characterised the function of RPS4Y1 in the context of the asthma-relevant processes, inflammation and fibrosis. No viable RPS4X knockouts could be generated. We highlight novel molecular mechanisms such as specific translation of IL6 and tenascin-C mRNA by RPS4Y1 containing ribosomes. Furthermore, an RPS4Y1-centric gene signature correlates with clinical lung function measurements, specifically in adult male asthma patients. These findings inform the current understanding of sex differences in asthma, as females do not produce the RPS4Y1 protein. Therefore, the pathologically relevant functions of RPS4Y1 may contribute to the complex sexually dimorphic pattern of asthma susceptibility and progression.
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ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms26136213