Biology subjects

Abrams, M. E.

Publications and source records attributed to Abrams, M. E..

5 recordsLinked to original sources

bioRxiv2025

Multiplex-edited mice recapitulate woolly mammoth hair phenotypes

The woolly mammoth (Mammuthus primigenius) possessed a thick woolly coat and other cold-adaptive traits that enabled survival in harsh arctic environments. Current de-extinction efforts focus on genetically modifying the closely related Asian elephant to express woolly mammoth traits. In this study, we establish a multiplex-edited mouse model with modifications in genes associated with hair morphology and lipid metabolism, enabling insights into traits involved in developing woolly hair textures. Our optimized workflows achieved high editing efficiencies and produced genetically modified mice with simultaneous editing of up to seven different genes. Selected modifications include loss-of-function mutations in Fgf5, Tgm3, and Fam83g, among others. The resulting mice display exaggerated hair phenotypes including curly, textured coats, and golden-brown hair. This study advances methods of rapid establishment of complex genetic models. These approaches inform de-extinction efforts and research involving the genetic basis of mammalian hair development.

genetics↗

bioRxiv2022

A concerted mechanism involving ACAT and SREBPs by which oxysterols deplete accessible cholesterol to restrict microbial infection

Most of the cholesterol in the plasma membranes (PMs) of animal cells is sequestered through interactions with phospholipids and transmembrane domains of proteins. However, as cholesterol concentration rises above the PMs sequestration capacity, a new pool of cholesterol, called accessible cholesterol, emerges. The transport of accessible cholesterol between the PM and the endoplasmic reticulum (ER) is critical to maintain cholesterol homeostasis. This pathway has also been implicated in the suppression of both bacterial and viral pathogens by immunomodulatory oxysterols. Here, we describe a mechanism of depletion of accessible cholesterol from PMs by the oxysterol 25-hydroxycholesterol (25HC). We show that 25HC-mediated activation of acyl coenzyme A: cholesterol acyltransferase (ACAT) in the ER creates an imbalance in the equilibrium distribution of accessible cholesterol between the ER and PM. This imbalance triggers the rapid internalization of accessible cholesterol from the PM, which is sustained for long periods of time through 25HC-mediated suppression of SREBPs. In support of a physiological role for this mechanism, 25HC failed to suppress Zika virus and human coronavirus infection in ACAT-deficient cells, and Listeria monocytogenes infection in ACAT-deficient cells and mice. We propose that selective depletion of accessible PM cholesterol triggered by ACAT activation and sustained through SREBP suppression underpins the immunological activities of 25HC and a functionally related class of oxysterols.

cell biology↗

bioRxiv2021

Over-expression Screen of Interferon-Stimulated Genes Identifies RARRES3 as a Restrictor of Toxoplasma gondii Infection

Toxoplasma gondii is an important human pathogen infecting an estimated 1 in 3 people worldwide. The cytokine interferon gamma (IFN{gamma}) is induced during infection and is critical for restricting T. gondii growth in human cells. Growth restriction is presumed to be due to the induction interferon stimulated genes (ISGs) that are upregulated to protect the host from infection. Although there are hundreds of ISGs induced by IFN{gamma}, their individual roles in restricting parasite growth in human cells remain somewhat elusive. To address this deficiency, we screened a library of 414 IFN{gamma} induced ISGs to identify factors that impact T. gondii infection in human cells. In addition to IRF1, which likely acts through induction of numerous downstream genes, we identified RARRES3 as a single factor that restricts T. gondii infection by inducing premature egress of the parasite in multiple human cell lines. Overall, while we successfully identified a novel IFN{gamma} induced factor restricting T. gondii infection, the limited number of ISGs capable of restricting T. gondii infection when individually expressed suggests that IFN{gamma} mediated immunity to T. gondii infection is a complex, multifactorial process.

microbiology↗

bioRxiv2019

The mechanisms of dynamin-actin interaction

Cell-cell fusion is an indispensable process in the conception, development and physiology of multicellular organisms. Here we demonstrate a direct and noncanonical role for dynamin, best known as a fission GTPase in endocytosis, in cell-cell fusion. Our genetic and cell biological analyses show that dynamin colocalizes within the F-actin-enriched podosome-like structures at the fusogenic synapse, which is required for generating invasive membrane protrusions and myoblast fusion in vivo, in an endocytosis-independent manner. Biochemical, negative stain EM and cryo-electron tomography (cryo-ET) analyses revealed that dynamin forms helices that directly bundles actin filaments by capturing multiple actin filaments at their outer rim via interactions with dynamins proline-rich domain. GTP hydrolysis by dynamin triggers disassembly of the dynamin helix, exposes the sides of the actin filaments, promotes dynamic Arp2/3-mediated branched actin polymerization, and generates a mechanically stiff actin network. Thus, dynamin functions as a unique actin-bundling protein that enhances mechanical force generation by the F-actin network in a GTPase-dependent manner. Our findings have universal implications for understanding dynamin-actin interactions in various cellular processes beyond cell-cell fusion.

cell biology↗

bioRxiv2017

Actin assembly-inducing protein ActA promotes FcγRIa-mediated Listeria internalization

Listeria monocytogenes is a Gram-positive intracellular pathogen and the causative agent of human listeriosis. While the ability of L. monocytogenes to enter and survive in professional phagocytes is critical to establish a successful infection, mechanisms of invasion are poorly understood. Our previous investigation into the role of type I interferon-stimulated genes in bacterial infection revealed that the human immunoglobulin receptor Fc{gamma}RIa served as a L. monocytogenes invasion factor. Fc{gamma}RIa-mediated L. monocytogenes entry occurred independently of immunoglobulin interaction or bacterial internalins. However, the bacterial determinants that mediate Fc{gamma}RIa interaction remain unclear. Using a comparative genomics approach, we identify actin assembly-inducing protein ActA as a pathogen specific ligand of Fc{gamma}RIa. Fc{gamma}RIa enhanced entry of pathogenic L. monocytogenes and L. ivanovii strain but not non-pathogenic L. innocua. We found that the major virulence regulator PrfA is required for pathogen entry into Fc{gamma}RIa-expressing cells and identify its gene target actA as the critical Listeria ligand. ActA alone was sufficient to promote entry into Fc{gamma}RIa-expressing cells, and this function is independent of its actin nucleating activity. Together, these studies present an unexpected role of ActA beyond its canonical function in actin-based motility and expand our understanding of Listeria strategies for host cell invasion.\n\nImportanceListeria monocytogenes is a food-borne bacterial pathogen and a causative agent of listeriosis with up to 50% mortality rate in immunocompromised individuals. While the mechanisms of Listeria entry into non-phagocytic cells have been extensively characterized, the details of phagocytic cell invasion are still poorly understood. We have recently discovered that human immunoglobulin receptor Fc{gamma}RIa mediates Listeria uptake by monocytic cells. This process occurred independently of canonical immunoglobulin interactions as well as classic Listeria internalization factors. Importantly, molecular determinants of Listeria-Fc{gamma}RIa interaction leading to bacterial entry, remained unknown. In this study, we demonstrate that Listeria virulence factor actin-assembly inducing protein ActA is required for Fc{gamma}RIa-mediated entry. Further, ActA was found to be sufficient for the internalization, suggesting its role as a bacterial ligand of Fc{gamma}RIa. Together, these findings expand our knowledge of mechanisms that Listeria has evolved to exploit cellular signaling pathways and immune defense of the host.

microbiology↗