Biology subjects

Bello, C.

Publications and source records attributed to Bello, C..

5 recordsLinked to original sources

bioRxiv2026

Protein Folding Interference Enables Selective Cyclin D1 Degradation

Cyclin D1 is a central regulator of cell-cycle progression and a compelling therapeutic target in cancer, yet its non-enzymatic function, limited ligandability, and rapid turnover have hindered direct pharmacological intervention. Here we show that these limitations can be overcome by targeting a transient conformational state populated during protein folding. Computational reconstruction of the Cyclin D1 folding landscape enabled the identification of a ligandable folding intermediate that served as the basis for structure-guided discovery of small molecules inducing selective degradation of nascent Cyclin D1. Orthogonal computational, biophysical, and cellular studies support the proposed mechanism, linking engagement of the folding intermediate to selective degradation of newly synthesized Cyclin D1. Pharmacological folding interference suppressed Cyclin D1 signaling, inhibited tumor cell proliferation, produced antitumor activity in vivo, and retained efficacy in a model of acquired resistance to CDK4/6 inhibition. Together, our findings establish a rational strategy for directly targeting Cyclin D1. More broadly, they suggest that the conformational landscape explored during protein folding represents an untapped reservoir of therapeutic opportunities, expanding small-molecule discovery beyond the native structures that have traditionally defined the druggable proteome.

biochemistry↗

bioRxiv2026

Beyond biodiversity loss defaunation: cascades effects in zoonotic disease ecology

Defaunation, defined as the loss or severe decline of animal populations, is increasingly recognized as a major dimension of global environmental change, yet its role in zoonotic disease ecology remains poorly understood. Although defaunation significantly influences ecological dynamics, current metrics often focus on species loss without fully addressing its cascading impacts, which can affect ecological processes such as zoonotic disease transmission. In this perspective, we propose a defaunation-cascade framework linking anthropogenic pressure to zoonotic pathogen dynamics through four ecological steps: host trait filtering, abundance restructuring, interaction rewiring, and altered pathogen circulation or proliferation, and potential spillover hazard. We illustrate this framework by using a global review of empirical studies and combining georeferenced data on disease prevalence with environmental and human-related factors. Our exploratory models suggest pathogen-specific associations: parasitic and bacterial prevalence were more strongly associated with anthropogenic pressure and mammal diversity metrics, whereas viral prevalence showed weaker support. We contend that incorporating defaunation cascades into One Health surveillance will improve ecological understanding of pathogen circulation and enhance the ecological accuracy and predictive power of zoonotic disease models, thereby identifying landscapes where faunal simplification may elevate spillover hazard.

ecology↗

bioRxiv2024

A probabilistic view of forbidden links: their prevalence and their consequences for the robustness of mutualistic networks

The presence in ecological communities of unfeasible species interactions, termed forbidden links, due to physiological or morphological exploitation barriers has been long debated, but little direct evidence has been found. Forbidden links are likely to make ecological communities less robust to species extinctions, stressing the need to assess their prevalence. Here, we used a dataset of plant-hummingbird interactions, coupled with a Bayesian hierarchical model, to assess the importance of exploitation barriers in determining species interactions. We found evidence for exploitation barriers between flowers and hummingbirds across the 32 studied communities, however, the proportion of forbidden links changed drastically among communities, because of changes in trait distributions. The higher the proportion of forbidden links, the more they decreased network robustness, because of constraints on interaction rewiring. Our results suggest that exploitation barriers are not rare in plant-hummingbird communities and have the potential to limit the rescue of species experiencing partner extinction.

ecology↗

bioRxiv2020

Role of astrogial Connexin 43 in pneumococcal meningitis and pneumolysin cytotoxicity

Introductory paragraphStreptococcus pneumoniae or pneumococcus (PN) is a major causative agent of bacterial meningitis with high mortality in young infants and elderly people. The mechanism underlying PN crossing of the blood brain barrier (BBB) remains poorly understood. Here, we show that the gap junctional component connexin 43 expressed in astrocytes (aCx43) plays a major role in PN meningitis. Following intravenous PN challenge, mice deficient for aCx43 developed milder symptoms and showed severely reduced bacterial counts in the brain. We show a role for aCx43 in the PN-induced fragmentation of astrocytic GFAP filaments associated with bacterial translocation across endothelial vessels and replication in the brain cortex. aCx43 triggers the PN- and Ply-dependent GFAP fragmentation and nuclear shrinkage in in vitro cultured astrocytes. We showed that purified pneumolysin (Ply) co-opted Cx43 to promote the permeabilization and cytosolic calcium (Ca2+) increase of host cells, a process sensitive to extracellular ATP depletion. These results point to aCx43 as a major player during bacterial meningitis and extend cytolytic mechanisms implicating other host cell plasma membrane channels proposed for small pore-forming toxins, to Ply, a cholesterol-dependent cytolysin, at concentrations relevant to bacterial infection.

microbiology↗

bioRxiv2019

Vinculin targeting by Shigella IpaA promotes stable cell adhesion independent of mechanotransduction

The Shigella effector IpaA co-opts the focal adhesion protein vinculin to promote bacterial invasion. Here, we show that IpaA triggers an unreported mode of vinculin activation through the cooperative binding of its three vinculin-binding sites (VBSs) leading to vinculin oligomerization via its D1 and D2 head subdomains and highly stable adhesions resisting actin relaxing drugs. Using cross-linking mass spectrometry, we found that while IpaA VBSs1-2 bound to D1, IpaA VBS3 interacted with D2, a subdomain masked to other known VBSs. Structural modeling indicated that as opposed to canonical activation linked to interaction with D1, these combined VBSs interactions triggered major allosteric changes leading to D1D2 oligomerization. A cysteine-clamp preventing these changes and D1D2 oligomerization impaired growth of vinculin microclusters and cell adhesion. We propose that D1D2-mediated vinculin oligomerization occurs during the maturation of adhesion structures to enable the scaffolding of high-order vinculin complexes, and is triggered by Shigella IpaA to promote bacterial invasion in the absence of mechanotransduction. SummaryThe Shigella IpaA effector binds to cryptic vinculin sites leading to oligomerization via its head domain. This vinculin oligomerization mode appears required for the maturation and strengthening of cell adhesion but is co-opted by invasive bacteria independent of actomyosin contractility.

microbiology↗