Biology subjects

Iversen, L.

Publications and source records attributed to Iversen, L..

3 recordsLinked to original sources

bioRxiv2023

Rare coding variants in NOX4 link high superoxide levels to psoriatic arthritis mutilans

Psoriatic arthritis mutilans (PAM) is the rarest and most severe form of psoriatic arthritis. PAM is characterized by erosions of the small joints of hands and feet and osteolysis leading to joint disruption. Despite its severity, the underlying mechanisms are unknown, and no candidate susceptibility genes have hitherto been identified. We aimed to investigate the genetic basis of PAM. We performed massive parallel sequencing of sixty-one patients genomes from the PAM Nordic cohort. We validated the rare variants found by Sanger sequencing and genotyped additional psoriasis, psoriatic arthritis, and control cohorts. We then tested the role of the variants using in vivo and in vitro models. We found rare variants with a minor allele frequency (MAF) below 0.0001 in the NADPH oxidase 4 (NOX4) in four patients. In silico predictions show that the identified variants are potentially damaging. NOXs are the only enzymes producing reactive oxygen species (ROS). ROS are highly reactive molecules important role in the regulation of signal transduction. NOX4 is specifically involved in the differentiation of osteoclasts, the cells implicated in bone resorption. Functional follow-up studies using cell culture, zebrafish models, and measurement of ROS in patients uncovered that the NOX4 variants found in this study increase the levels of ROS both in vitro and in vivo. We propose NOX4 as the first candidate susceptibility gene for PAM. Our study links high levels of ROS caused by NOX4 variants to the development of PAM, opening the possibility for a potential therapeutic target.

genetics↗

bioRxiv2022

Activation and inhibition of the C-terminal kinase domain of p90 ribosomal S6 kinases

The p90 ribosomal S6 kinases (RSKs) contain two distinct catalytic kinase domains, the N-terminal and C-terminal kinase domains (NTKD and CTKD, respectively). The activation of CTKD is regulated by phosphorylation by extracellular signal-regulated kinase (ERK1/2) and an autoinhibitory L helix. Through a mutational series in vitro of the RSK CTKDs, we found a complex mechanism lifting autoinhibition that led us to design constitutively active RSK CTKDs. These are based on a phosphomimetic mutation and a C-terminal truncation (e.g. RSK2 T577E D694*) where a high activity in absence of ERK phosphorylation is obtained. Using these constructs, we characterize IC50 values of ATP-competitive inhibitors and provide a setup for determining specificity constants (kinact/Ki) of covalent CTKD inhibitors.

biochemistry↗

bioRxiv2019

High-throughput RNA sequencing from paired lesional- and non-lesional skin reveals major alterations in the psoriasis circRNAome

BackgroundPsoriasis is a chronic inflammatory skin disease characterized by hyperproliferation and abnormal differentiation of keratinocytes. It is one of the most prevalent chronic inflammatory skin condition in adults worldwide, with a considerable negative impact on quality of life. Circular RNAs (circRNAs) are a recently identified type of non-coding RNA with diverse cellular functions related to their exceptional stability. In particular, some circRNAs can bind and regulate microRNAs (miRNAs), a group of RNAs that play a role in the pathogenesis of psoriasis. The aim of this study was to characterize the circRNAome in psoriasis and to assess potential correlations to miRNA expression patterns.\n\nResultsUsing high-throughput RNA-sequencing (RNA-seq) and NanoString nCounter technology, we found a substantial down-regulation of circRNA expression in lesional skin compared to non-lesional skin from psoriasis patients. We saw that this mainly applies to the epidermis by analyzing laser capture microdissected tissues and by RNA chromogenic in situ hybridization (CISH). We also found that the majority of the circRNAs were downregulated independent of their corresponding linear host genes. The observed downregulation of circRNAs in psoriasis was not due to altered expression levels of factors known to affect circRNA biogenesis, nor because lesional skin contained an increased number of inflammatory cells such as lymphocytes. Finally, we saw that the overall differences in available miRNA binding sites on the circRNAs between lesional and non-lesional skin did not correlate with differences in miRNA expression patterns.\n\nConclusionsWe have performed the first genome-wide circRNA profiling of paired lesional and non-lesional skin from psoriasis patients and revealed that circRNAs are much less abundant in the lesional samples. Whether this is a cause or a consequence of the disease remains to be revealed, however, we found no evidence that the loss of miRNA binding sites on the circRNAs could explain differences in miRNA expression reported between lesional and non-lesional skin.

molecular biology↗