Biology subjects

Cahill, S.

Publications and source records attributed to Cahill, S..

4 recordsLinked to original sources

bioRxiv2025

MARCO is an IFN-restricted immunometabolic decoy LPS receptor

Intracellular sensing of lipopolysaccharide (LPS) is an essential component of pathogen detection that governs the innate immune response. However, how this process is controlled to maintain homeostasis and resolve inflammation is unclear. Here, we show that MARCO is a decoy LPS sensor crucial for restraining caspase 11 activity and the non-canonical inflammasome. Remarkably, MARCO expression is controlled by a non-canonical TLR signaling pathway involving the metabolite itaconate, the autophagy adaptor protein p62, and the transcription factor NRF2. In the presence of IFN, non-canonical TLR signaling is impaired and NRF2 dependent gene expression is terminated. Thus, impairing MARCO expression and licensing optimal activation of the non-canonical inflammasome. Loss of MARCO augments non-canonical inflammasome activation and sensitizes mice to septic shock. Together, this study identifies MARCO as a previously unknown LPS sensor that is regulated by a non-canonical TLR signaling pathway and reveals an intricate homeostatic switch that allows for optimal immune responses and resolution of inflammation.

immunology↗

bioRxiv2024

Alternative cGAS signaling promotes Herpes simplex encephalitis

During infection, foreign DNA is sensed by cyclic GMP-AMP synthase (cGAS) leading to the production of cGAMP, STING-dependent type I interferon and proinflammatory cytokine expression, and autophagy. To prevent a response to self-DNA, cGAS activity is tightly regulated. Dysregulation of cGAS underpins interferonopathies, such as Aicardi-Goutieres syndrome, as well as Lupus and neurodegenerative diseases like Parkinsons disease. Thus, cGAS and its product cGAMP are therapeutic targets. However, if cGAS functions independently of cGAMP signaling is undefined. Here, we identified an alternative signaling pathway that cGAS engages independent of cGAMP synthesis. We demonstrate that alternative cGAS signaling promotes hyperexpression of CXCL1 and enhanced neutrophil recruitment that facilitates viral dissemination during herpes simplex encephalitis. Our study is the first report of an alternative cGAS response independent of cGAMP highlighting a previously uncharacterized scaffold function for cGAS.

immunology↗

bioRxiv2024

Characterizing interactions in the nuclear pore complex transporter using novel site-specific deuteration and SANS

We describe an unprecedented SANS/solvent matched experiment with the aim of providing a meso-scale dynamic structural description of fuzzy complexes such as those formed by nuclear transport factors as they ferry cargo across the nuclear pore complex, whose description is normally limited by the large number of states and rapid time scales of interconversion. These contain repeat short linear interaction domains which are common features of many intrinsically disordered functional proteins - e.g., transcriptional regulators, and RNA-interaction domains associated with liquid-liquid phase separated non-membranous organelles. The novel approach uses site-specific deuteration, SANS, and model fitting to provide changes to average spatial distributions between interacting domains of FG Nups upon binding to the nuclear transport factor NTF2. The results support the fully disordered nature of phenylalanyl-glycyl repeats within FG Nups in their interactions with the nuclear transport factor in vitro, as well as the absence of significant inter-aromatic contacts, or of interchain linkage in complexes.

biophysics↗

bioRxiv2023

Glutamylation of Npm2 and Nap1 acidic disordered regions increases DNA charge mimicry to enhance chaperone efficiency

Histone chaperones-structurally diverse, non-catalytic proteins enriched with acidic intrinsically disordered regions (IDRs)-protect histones from spurious nucleic acid interactions and guide their deposition into and out of nucleosomes. Despite their conservation and ubiquity, the function of the chaperone acidic IDRs remains unclear. Here, we show that the Xenopus laevis Npm2 and Nap1 acidic IDRs are substrates for TTLL4 (Tubulin Tyrosine Ligase Like 4)-catalyzed post-translational glutamate-glutamylation. We demonstrate that, to bind, stabilize, and deposit histones into nucleosomes, chaperone acidic IDRs function as DNA mimetics. Our biochemical, computational, and biophysical studies reveal that glutamylation of these chaperone polyelectrolyte acidic stretches functions to enhance DNA electrostatic mimicry, promoting the binding and stabilization of H2A/H2B heterodimers and facilitating nucleosome assembly. This discovery provides insights into both the previously unclear function of the acidic IDRs and the regulatory role of post-translational modifications in chromatin dynamics.

biochemistry↗