CYRI1-mediated inhibition of RAC1 signalling restricts Salmonella Typhimurium infection

Yuki, K. E.; Marei, H.; Fiskin, E.; Eva, M. M.; Gopal, A. A.; Schwartzentruber, J. A.; Majewski, J.; Cellier, M.; Mandl, J. N.; Vidal, S. M.; Malo, D.; Dikic, I.

doi:10.1101/238733

bioRxiv · 10.1101/238733

CYRI1-mediated inhibition of RAC1 signalling restricts Salmonella Typhimurium infection

Yuki, K. E.·Marei, H.·Fiskin, E.·Eva, M. M.·Gopal, A. A.·Schwartzentruber, J. A.·Majewski, J.·Cellier, M.·Mandl, J. N.·Vidal, S. M.·Malo, D.·Dikic, I.

View original source ↗Export metadata ↓

Abstract

Salmonella presents a global public health concern. Central to Salmonella pathogenicity is an ability to subvert host defence mechanisms through bacterial effectors that target key host proteins implicated in restricting infection. Thus, to gain insight into host-pathogen interactions governing Salmonella infection, a thorough understanding of host defence mechanisms is needed. To tackle this, we performed an in vivo genome-wide ENU mutagenesis screen to uncover novel host defence proteins. Through this screen we identified an uncharacterised protein, which we name CYRI1 (CYFIP-related RAC1 Interacting protein 1) that serves as a Salmonella resistance factor. We show that CYRI1 binds to the small GTPase RAC1 through a conserved domain present in CYFIP proteins, which are known RAC1 effectors that stimulate actin polymerisation. However, unlike CYFIP proteins, CYRI1 negatively regulates RAC1-driven actin cytoskeleton remodelling, thereby attenuating processes such as phagocytosis and cell migration. This, in turn, enables CYRI1 to counteract Salmonella at various stages of infection, including bacterial entry into epithelial cells, internalisation into myeloid-derived phagocytes as well as phagocyte-mediated bacterial dissemination. Together, this outlines a novel host defence mechanism that is crucial for determining bacterial fate.

Explore related subjects

cell biology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Yuki, K. E., Marei, H., Fiskin, E., Eva, M. M., Gopal, A. A., Schwartzentruber, J. A., Majewski, J., Cellier, M., Mandl, J. N., Vidal, S. M., Malo, D., Dikic, I.. 2017-12-22. CYRI1-mediated inhibition of RAC1 signalling restricts Salmonella Typhimurium infection. https://doi.org/10.1101/238733

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Spatiotemporal mapping of endothelial proliferative response in acute chemical liver injury

Endothelial cells are major contributors to liver injury response, regeneration, and chronic liver disease. Previous studies identified a proliferative endothelial response to acute liver injury; however, a comprehensive characterization of this adaptive response is missing. We have developed a novel pipeline for spatiotemporal analysis of proliferative response in the liver. We demonstrate that endothelial cells enter the cell cycle upon acute centrilobular injury with a delay compared to hepatocytes and in a spatially distinct pattern from hepatocytes. We show that endothelial cycling predominantly occurs in the pericentral zone, while hepatocyte cycling occurs uniformly throughout the lobule. Endothelial cycling in injured livers leads to heightened clonal expansion, and to serial division rarely observed in homeostatic livers. Consequently, injured lobules exhibit endothelial overabundance during regeneration. Our study provides an in-depth characterization of endothelial proliferative response to liver injury and establishes a novel pipeline for spatiotemporal mapping of hepatic cell states.

cell biology↗

bioRxiv2026

Pathological levels of α-synuclein increase basal mitophagy in Parkinson's dopamine neurons

Elevated -synuclein results in mitochondrial dysfunction, however the exact mechanism is poorly understood. -Synuclein localises to multiple subcellular sites including mitochondria, where it binds anionic lipids which regulate mitochondrial dynamics through DRP1. We hypothesised that pathogenic levels of -synuclein lead to dysregulation of mitophagy and lipid-dependent mitochondrial dynamics, causing mitochondrial and neuronal dysfunction. Using induced pluripotent stem cell-dopamine neurons (iPSC-DANs) carrying the -synuclein gene triplication mutation (SNCA-Trp) which causes an early-onset form of Parkinson's disease (PD), we established that elevated -synuclein increased basal mitophagy compared to healthy controls and overall loss of mitochondrial mass. This was associated with accumulation of basal mitophagy receptors BNIP3 and NIX and decreased proteasome activity, and was independent of PINK1-Parkin mitophagy. We identified reduced mitochondrial gene expression by single cell RNAseq, mirroring heightened mitophagy and mitochondrial depletion. We found increased levels of DRP1-dependent mitochondrial fission and perturbed levels of anionic lipids, including cardiolipin and phosphatidic acid, two lipids which directly bind to -synuclein. Pharmacological inhibition of DRP1 reversed the excessive basal mitophagy in SNCA-Trp neurons and restored deficits in cellular ATP and calcium release. Finally, we assessed neuronal function and found that impairment of mitochondrial dysfunction by elevated -synuclein led to reductions in neuronal firing activity. Inhibition of DRP1 rescued the neuronal activity deficit in SNCA-Trp neurons, suggesting that relieving - instead of increasing - mitophagy pressure may be beneficial in -synuclein-driven PD.

cell biology↗

bioRxiv2026

Effect of Varying Cigarette Smoke Concentrations and Durations on the Retinal Pigment Epithelium

Dry age-related macular degeneration (AMD) is a leading cause of blindness in the elderly, and treatment options are limited. Cigarette smoke (CS), the primary modifiable environmental risk factor for AMD, damages the retinal pigment epithelium (RPE) by inducing oxidative stress, which in turn activates multiple stress response pathways. Low levels of stress induce autophagy, a cell-recycling mechanism; moderate stress induces epithelial-mesenchymal transition (EMT); and high, sustained stress, once other cytoprotective pathways are exhausted, leads to cell death. All three pathways are implicated in AMD pathogenesis. Although CS is known to induce oxidative stress, its impact on these distinct stress response pathways remains understudied, and few studies have directly compared mouse and human RPE responses to the same stressor. Here, we examined the effect of varying concentrations and durations of cigarette smoke condensate (CSC) exposure on oxidative stress, autophagy, EMT, and cell death in ARPE-19 (human) and mouse RPE (MRPE) cells. Understanding which stress response pathways predominate at which CSC exposure levels may help guide the development of AMD treatments stratified by smoking history.

cell biology↗