Biology subjects

Karmi, O.

Publications and source records attributed to Karmi, O..

5 recordsLinked to original sources

bioRxiv2025

Functional characterization of immune cells in a cnidarian reveals an ancestral antiviral program

Examining early-branching animal phyla can help reconstructing the evolutionary origins of immune cells. Here, we characterized immune-related cell programs in embryos of the sea anemone Nematostella vectensis, a model of Cnidaria, which diverged [~]600 million years ago from other animals. Using a transgenic Nematostella reporter line expressing mCherry under the RLRb antiviral promoter, we identified a morphologically and transcriptomically distinct cell population activated by the viral mimic poly(I:C). These cells upregulate immune effector and regulator genes and show increased phagocytic activity. Bulk RNA sequencing of RLRb expressing cells and single-cell transcriptomics revealed gene regulatory programs expressed in specialized immune cells under basal conditions and upon activation. Comparing the Nematostella immune expression profile with that of stony corals treated with the immunostimulant 2'3'-Cyclic GMP-AMP demonstrated a conserved immune response across Hexacorallia. This study uncovers a novel cnidarian immune cell type involved in antiviral immunity, providing insights into the evolutionary history of innate immunity.

evolutionary biology↗

bioRxiv2025

Unraveling the molecular mechanism underlying the anticancer activity of CISD2/NAF-144-67

We recently reported on the development of a unique cancer-targeting peptide called NAF-144-67 (derived from CISD2/NAF-1). NAF-144-67 selectively permeates the plasma membrane (PM) of cancer cells, but not healthy cells, causing the activation of apoptotic and ferroptotic cell death pathways specifically in cancer cells. NAF-144-67 also targets and shrinks human breast and ovarian cancer tumors in a xenograft mice model system without any apparent side effects. Although the specific permeation of NAF-144-67 through cancer cell PMs was studied, and its cancer killing effects validated in vitro and in vivo, little is known about how NAF-144-67 exerts its biological activity once it enters cancer cells. Here, we report that NAF-144-67 targets the CISD2/NAF-1 protein of cancer cells and disrupts its homodimeric structure. We further reveal that a peptide derived from the same domain of the human CISD1 (mitoNEET; mNT19-42) protein, a close family member to CISD2, has no killing activity towards cancer cells, and that dimers of NAF-144-67 (at two different orientations) have higher anticancer activity compared to monomeric NAF-144-67. Our findings shed new light on the biological activity of NAF-144-67 and bring it closer to becoming a potential new anticancer drug.

cancer biology↗

bioRxiv2024

Targeting primary and metastatic ovarian cancer with a peptide derived from the human NAF-1/CISD2 protein

Ovarian cancer is the most fatal cancer of female reproductive organs. Ovarian cancer is typically diagnosed at a late stage, after metastasis occurred, leading to a 5-years relative survival rate of only [~]5%. Here, we demonstrate the anti-ovarian cancer properties of a peptide derived from the human protein CISD2/NAF-1 (3D-NAF-144-67-6K). This peptide selectively permeates the plasma membrane of ovarian cancer SKOV-3 cells without affecting healthy cells. 3D-NAF-144-67-6K targets and destroys the cancer cells mitochondria which leads to cancer cell death. In vivo studies of mice carrying xenograft tumours of SKOV-3 showed that the peptide significantly decreased the overall size and growth rate of both primary and metastatic ovarian cancer tumours. We further show that 3D-NAF-144-67-6K has a broad-spectrum anticancer activity targeting leukaemia, brain, and pancreas cancer cells. Our study suggests that 3D-NAF-144-67-6K could be used, alone or in drug combinations, to treat ovarian cancer and improve patient survival.

cancer biology↗

bioRxiv2023

Induction of apoptosis by double-stranded RNA was present in the last common ancestor of cnidarian and bilaterian animals

Apoptosis, a major form of programmed cell death, is an essential component of host defense against invading intracellular pathogens. Viruses encode inhibitors of apoptosis to evade host responses during infection, and to support their own replication and survival. Therefore, hosts and their viruses are entangled in a constant evolutionary arms race to control apoptosis. Until now, apoptosis in the context of the antiviral immune system has been almost exclusively studied in vertebrates. This limited phyletic sampling makes it impossible to determine whether a similar mechanism existed in the last common ancestor of animals. Here, we established assays to probe apoptosis in the sea anemone Nematostella vectensis, a model species of Cnidaria, a phylum that diverged approximately 600 million years ago from the rest of animals. We show that polyinosinic:polycytidylic acid (poly I:C), a synthetic long double-stranded RNA mimicking viral RNA and a primary ligand for the vertebrate RLR melanoma differentiation-associated protein 5 (MDA5), is sufficient to induce apoptosis in N. vectensis. Furthermore, at the transcriptomic level, apoptosis related genes are significantly enriched upon poly(I:C) exposure in N. vectensis as well as bilaterian invertebrates. Our phylogenetic analysis of caspase family genes in N. vectensis reveals conservation of all four caspase genes involved in apoptosis in mammals and revealed a cnidarian-specific caspase gene which was strongly upregulated. Altogether, our findings suggest that apoptosis in response to a viral challenge is a functionally conserved mechanism that can be traced back to the last common ancestor of Bilateria and Cnidaria.

evolutionary biology↗

bioRxiv2023

CISD3 is required for Complex I function, mitochondrial integrity, and skeletal muscle maintenance

Mitochondria play a central role in muscle metabolism and function. In skeletal muscles, a unique family of iron-sulfur proteins, termed CISD proteins, support mitochondrial function. The abundance of these proteins declines with aging leading to muscle degeneration. Although the function of the outer mitochondrial proteins CISD1 and CISD2 has been defined, the role of the inner mitochondrial protein CISD3, is currently unknown. Here we show that CISD3 deficiency in mice results in muscle atrophy that shares proteomic features with Duchenne Muscular Dystrophy. We further reveal that CISD3 deficiency impairs the function and structure of skeletal muscle mitochondria, and that CISD3 interacts with, and donates its clusters to, Complex I respiratory chain subunit NDUFV2. These findings reveal that CISD3 is important for supporting the biogenesis and function of Complex I, essential for muscle maintenance and function. Interventions that target CISD3 could therefore impact muscle degeneration syndromes, aging, and related conditions.

cell biology↗