Biology subjects

Chernomordik, L. V.

Publications and source records attributed to Chernomordik, L. V..

4 recordsLinked to original sources

bioRxiv2026

MULTIVALENT ACE2 ENGAGEMENT ACTIVATES PIEZO1-SPHINGOMYELINASE SIGNALING IN SARS-COV-2 SPIKE-MEDIATED CELL-CELL FUSION

SARS CoV 2 Spike not only fuses the viral envelope with host membranes to deliver viral RNA but also drives syncytium formation, a process that may contribute to viral spread and pulmonary pathology. Although the conformational transitions in Spike triggered by ACE2 engagement are well characterized, the host cell signaling events initiated by Spike-ACE2 interactions remain less understood. Here, we examine how Spike activates acid sphingomyelinase (ASM) in ACE2 expressing A549 cells and how this activity promotes cell-cell fusion. Using ASM-deficient and complemented cells, exogenous ceramide, pharmacological perturbations, and a split-NeonGreen fusion assay, we support a fusion-promoting pathway in which Spike-induced ACE2 clustering activates the mechanosensitive ion channel PIEZO1, triggering lysosomal exocytosis. Secreted ASM, together with intracellular neutral sphingomyelinase, generates ceramide that enhances syncytium formation, likely through activation of protein phosphatases PP1 and PP2A. Our results suggest that these phosphatases promote fusion by facilitating actin cortex detachment and reducing actomyosin tension through dephosphorylation of ERM proteins. Our findings highlight dynamic changes in membrane lipid composition and membrane-cytoskeleton interactions as regulators of fusion and signaling in SARS-CoV-2 infection and, potentially, other viral and cellular systems.

cell biology↗

bioRxiv2025

Elevated surface La promotes hyperfusion and contributes to impaired resorption in osteopetrosis.

The skeleton is a living, biological tissue responding to the biomechanical demands placed upon it throughout life. The individual bones creating this physiological system are each shaped by a multinucleated cell type - the osteoclast - that sculpts each bone in collaboration with local cellular partners, which offer chemical and even tactile feedback of many sorts. Unfortunately, the perturbation of osteoclast formation and function underpins a broad range of human skeletal pathologies, including osteopetrosis - a systemic pathology characterized by impaired osteoclast resorption leading to skeletal thickening, brittle bones, frailty, and lethality. Here, we describe a molecular dysfunction observed in murine and human models of two forms of osteoclast-rich, autosomal recessive osteopetrosis, and our approach for exploiting this molecular dysfunction to correct pathologic osteoclast hyperfusion and resorptive impairment. We find that La - a manager of osteoclast fusion and subsequent resorptive activity - is greatly elevated at the surface of osteoclasts upon loss of SNX10 or OSTM1. Using inhibitory antibodies, we suppress excessive La surface function in these mutant osteoclasts, impede osteopetrotic hyperfusion and restore osteoclast resorptive function. We share these observations as proofs-of-principle that osteoclast fusion represents a viable therapeutic target for addressing osteoclast dysfunction in diseases underpinned by excessive osteoclast multinucleation and perturbed resorptive function.

cell biology↗

bioRxiv2022

An inducible explant model for dissecting osteoclast-osteoblast coordination in health and disease.

Metabolic bone diseases are a collection of disorders resulting in diminished skeletal integrity and changes in bone mass due to perturbations in the life-long process of bone remodeling. Perturbations in the number, size and nuclear multiplicity of osteoclasts underpin the development of diverse metabolic bone diseases that impact >13% of adults over age 50 world-wide. Each metabolic bone disease (e.g., osteoporosis, Pagets disease, fibrous dysplasia (FD), osteopetrosis) presents with unique phenotypes, rises from distinct etiologies and progresses with disparate severities, but all are underpinned by a breakdown in osteoclast formation/function. These perturbations of osteoclast formation/function either stem from or cause dysfunctional osteoclast-osteoblast coordination. Unfortunately, a mechanistic understanding of osteoclast-osteoblast coordination and communication is lacking and represents a major barrier to understanding the biology underpinning bone remodeling and the development of effective treatments targeting this process. Here we have developed an inducible ex vivo culture model that models osteoclast-osteoblast coordination in the bone remodeling compartment. Doxycycline addition to cultures activates GsR201C expression and RANKL release from osteoprogenitors, which elicits the differentiation and fusion of neighboring preosteoclasts. In turn, multinucleated osteoclast formation promotes the proliferation of osteoprogenitors, accompanied by the robust release of RANK+ extracellular vesicles, all within [~]4 days. This system recapitulates many aspects of the complex osteoclast-osteoblast coordination required for the function of the bone remodeling compartment in both health and diseases underpinned by excessive osteoclast formation. Moreover, based on the ease of isolation, culture, reproducibility and the general adaptability of these cultures to a variety of assays, we expect that this new model will expedite the investigation of osteoclast-osteoblast coordination and osteoclast fusion in bone remodeling and offer a powerful tool for evaluating signaling cascades and novel therapeutic interventions in osteoclast-linked skeletal disease. One-Sentence SummaryConditional, inducible, ex vivo marrow explants offer a novel tool for studying osteoclast formation and osteoclast-osteoblast coordination in a rapid convenient culture model.

cell biology↗

bioRxiv2016

Arabidopsis HAP2/GCS1 is a gamete fusion protein homologous to somatic and viral fusogens

Cell-cell fusion is inherent to any form of sexual reproduction. Loss of HAPLESS 2/GENERATIVE CELL SPECIFIC 1 (HAP2/GCS1) proteins results in gamete fusion failure in different organisms but their exact role is unclear. Here we show that Arabidopsis HAP2/GCS1 expression in mammalian cells is sufficient to promote cell-cell fusion. Hemifusion and complete fusion depend on HAP2/GCS1 presence in both fusing cells. Furthermore, expression of HAP2 on the surface of pseudotyped vesicular stomatitis virus and on the target cells results in HAP2-dependent virus-cell fusion. This bilateral requirement can be bypassed by replacing the plant gene with C. elegans EFF-1 somatic cell fusogen in one of the fusing cells or the virus, indicating that HAP2/GCS1 and EFF-1 share a similar fusion mechanism. Structural modeling of the HAP2/GCS1 protein family predicts that they are homologous to EFF-1 and class II fusion proteins from enveloped viruses (e.g. dengue and Zika viruses). We name this superfamily FUSEXINS: FUSion proteins essential for sexual reproduction and EXoplasmic merger of plasma membranes. Thus, Fusexins unify the origin and evolution of sexual reproduction, enveloped virus entry into cells and somatic cell fusion.

cell biology↗