Biology subjects

Coyle, K.

Publications and source records attributed to Coyle, K..

3 recordsLinked to original sources

bioRxiv2025

Regulation of NFKBIZ by precise Regnase-1 endoribonuclease cleavage and subsequent uridylation

A conserved sequence in the 3'UTR of NFKBIZ mRNA has long been recognized as a regulator of cytokine production and interferon responses. We show that the endoribonuclease Regnase-1 controls NFKBIZ expression through a precise and modular RNA degradation mechanism. The structured core element undergoes specific endonucleolytic cleavage, while flanking upstream and downstream stem-loop modules, previously implicated in Regnase-1 recognition, act cooperatively to enhance cleavage efficiency by [~]25-fold. Following cleavage, the upstream fragment is rapidly uridylated, accelerating decay of the NFKBIZ open reading frame. This pathway explains how driver mutations - found in this RNA region - responsible for diffuse large B-cell lymphoma elevate NFKBIZ expression and how a segment of the SARS-CoV-2 genome - previously linked to NFKBIZ activation - suppresses Regnase-1 cleavage via hybridization to this regulatory RNA segment. Together, these findings define a mechanistic framework for Regnase-1-mediated control of NFKBIZ, linking its cleavage activity to both lymphomagenesis and viral pathogenesis.

biochemistry↗

bioRxiv2024

The Autonomic Nervous System (ANS)-Immune Network in People Living With HIV

PurposePre-clinical studies have demonstrated direct influences of the autonomic nervous system (ANS) on the immune system. However, it remains unclear if ANS-immune connections delineated in pre-clinical studies underlie the relationship between autonomic dysregulation and chronic inflammatory diseases in patients with HIV. This study had three aims: 1.) Examine the relationship between IL-6 and the parasympathetic/vagal component of baroreflex sensitivity (BRS-V) in people with HIV; 2.) Determine if the subtype and severity of HIV-autonomic neuropathy (AN) would predict distinct immunotypes; 3.) Compare the burden of non-AIDS-related co-morbidities between immunotypes. Methods79 adults with well-controlled HIV underwent a standard battery of autonomic function tests summarized as the Composite Autonomic Severity Score and vagal and adrenergic baroreflex sensitivity (BRS-V and BRS-A).1 Levels of immune biomarkers were measured in all participants using the Target 96 Inflammation Panel on the Olink proteomics platform and immunotypes were identified using unbiased, non-negative matrix factorization. Mass cytometry (CyTOF) was completed on a subset of participants with and without autonomic neuropathy (N = 10). ResultsReduced BRS-V predicted higher levels of IL-6 (p=0.002). A pro-inflammatory immunotype defined by elevations in type 1 cytokines (IL-6, IL-17) and increased numbers of CD8+ T-cells was associated with autonomic neuropathy characterized by deficits in sympathetic nervous system activity (aOR=4.7, p=0.017). This pro-inflammatory immunotype was older with a greater burden of co-morbidities. ConclusionDeficits in the parasympathetic/cardiovagal and the sympathetic nervous system are associated with inflammation and disease burden in people living with HIV. Future longitudinal research is needed to examine causality.

immunology↗

bioRxiv2023

Ribosome Quality Control Mechanism Mitigates the Cytotoxic Impacts of Ribosome Collisions Induced by 5-Fluorouracil

Translation of aberrant or damaged mRNAs results in ribosome stalling and collisions. The Ribosome Quality Control (RQC) mechanism detects collided ribosomes and removes aberrant mRNAs and nascent peptides, thus preventing their cytotoxic effects. Conversely, excessive or unresolved ribosome collisions can induce apoptosis. 5-Fluorouracil (5FU) forms the backbone of standard-of-care chemotherapeutic regimens for several types of cancer. Although best known for its incorporation into DNA and inhibition of thymidylate synthase, a major determinant of 5FUs anticancer activity is its incorporation into RNAs. Nevertheless, the mechanism(s) underlying RNA-dependent 5FU cytotoxicity and the cellular response to its impact on RNA metabolism remain unclear. Here, we report a key role for RQC in mitigating the cytotoxic effects of 5FU-induced dysregulation of mRNA translation. We show that acute 5FU treatment results in the rapid induction of the mTOR signalling pathway, an enhanced rate of mRNA translation initiation, and increased ribosome collisions that trigger RQC. We also found that RQC deficiency, caused by the depletion of ZNF598, results in increased 5FU-induced cell death, a phenotype that is reversed by inhibition of mTOR or repression of mRNA translation initiation. Importantly, 5FU treatment enhances the expression of key RQC factors, including ZNF598 and GIGYF2, via an mTOR-dependent post-translational regulation mechanism. This acute adaptation likely mitigates the cytotoxic consequences of increased ribosome collisions upon 5FU treatment. Overall, our data indicate a heretofore unknown mTOR-dependent mechanism that augments the RQC process, mitigating the cytotoxicity of 5FU and undermining its anticancer efficacy.

cell biology↗