Cerda, P. | bioRxiv Science

bioRxiv2026

ERK overstimulation leads to cell hyperproliferation in hereditary hemorrhagic telangiectasia landscape

Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular disorder caused by pathogenic variants in members of the BMP9/ALK1 signaling hub. In the present study we show that, regardless of whether the alterations are caused by reduced BMP9/ALK1 signaling (pathogenic variants in the ENG or ALK1 genes) or by overactivation of this pathway (such as the SMAD6 pathogenic variants), all are associated with increased endothelial cell (EC) proliferation and high levels of ERK MAPK activation in patient biopsies. We reproduced this phenotype in vitro in ECs lacking SMAD6 or after SMAD1 knockdown using siRNA. Loss of SMAD6 leads to dysregulation of the Notch pathway, with downregulation of phosphatases and consequent overstimulation of ERK. In normal ECs, BMP9 and Notch signaling inhibit ERK activity by upregulating PPP1R3C, a regulatory subunit of the PP1 phosphatase. Notably, BMP9-mediated inhibition of ERK is abolished when cells are transfected with siRNA targeting PPP1R3C. ERK hyperactivation was also observed in an HHT2 mouse model (ALK1-2loxP;Cdh5-CreERT2). Loss of both ALK1 alleles in adult mice leads to vascular failure and hemorrhages in the lung and intestine; these injuries are significantly reduced by treatment with the MEK/ERK inhibitor selumetinib. Overall, our work identifies a key role for ERK activation involved in HHT pathogenesis, suggesting that ERK inhibition may represent a promising therapeutic strategy for these patients. Translational PerspectiveHereditary hemorrhagic telangiectasia (HHTs) is a rare vascular disorder caused by mutations in members of the BMP9/ALK1 signaling hub. In the present study we show that all different forms of HHTs are associated with increased endothelial cell (EC) proliferation, which correlates with high levels of ERK activation in patient biopsies. ERK hyperactivation is also observed in an HHT2 mouse model in which loss of both ALK1 alleles in adult mice leads to vascular failure and hemorrhages in the lung and intestine. These injuries are significantly reduced by treatment with the MEK/ERK inhibitor selumetinib. Overall, our work identifies a key role for ERK activation in HHT pathogenesis, suggesting that ERK/MEK inhibitors may represent a promising therapeutic strategy for these patients.

pathology↗

bioRxiv2024

Increased host diversity limits bacterial generalism but may promote microbe-microbe interactions

Host-associated bacteria vary in their host breadth, which can impact ecological interactions. By colonizing diverse hosts, host generalists can have disproportionate ecological impacts. For bacteria, host generalism may advantageous, particularly when the availability of specific hosts is variable. It is unclear how much the ability to evolve generalism, by inhabiting diverse hosts, is constrained in host-associated bacteria. We hypothesized that constraints on bacterial generalism will differ depending on the availability of specific host species. To test this, we assessed patterns of diversity and specialization in the cloacal microbiomes of reptile communities from the temperate zone to the tropics, where the diversity and abundance of host species varies substantially. Within these communities, generalist taxa tended to be Proteobacteria, whereas specialists tended to be Firmicutes. We found that bacterial generalists were less prevalent in the highest diversity host communities, and in keeping with this, Proteobacteria were less diverse in these communities. Generalist taxa became relatively less widespread across host species only in the two most diverse host communities. We therefore conclude that the constraint on generalism is not driven by absolute incompatibility with some host species, but rather from competition with host adapted specialist lineages. In the high-diversity communities, we found that the successful generalists, typically Proteobacteria, were disproportionately likely to co-occur with one another across evolutionarily disparate hosts within the community. Our data indicate that bacterial lineages can adapt to the evolutionary pressures of high diversity host communities either by specializing on hosts or by forming cohorts of co-occurring bacterial lineages.

ecology↗