New therapeutics from Nature: The odd case of the bacterial cytotoxic necrotizing factor 1

Maroccia, Zaira; Loizzo, Stefano; Travaglione, Sara; Frank, Claudio; Fabbri, Alessia; Fiorentini, Carla

doi:10.1016/j.biopha.2018.02.140

Cited by 11 publications

(7 citation statements)

References 107 publications

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“…Whether the alterations of pRb and HMGA2 expression result in an increase of CNF1 resistance requires further examination. It is worth noting that CNF1 processes a promising potential in therapy for glioma tumor, neuropathic pain and other neurological disorders 56 , whether the therapeutic treatment will confer resistance to CNF1 in host cell or tissue remains unknown. Further deciphering the resistance mechanism to CNF1 will not only help to understand the role of CNF1 in cell fate determination, but may also enable the identification of novel therapeutic agents indifferent to these resistance mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Reversible senescence of human colon cancer cells after blockage of mitosis/cytokinesis caused by the CNF1 cyclomodulin from Escherichia coli

Zhang

Aung

Uhlin

et al. 2018

Sci Rep

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Cytotoxic necrotizing factor 1 (CNF1), a protein toxin produced by extraintestinal pathogenic Escherichia coli, activates the Rho-family small GTPases in eukaryotic cell, thereby perturbing multiple cellular functions. Increasing epidemiological evidence suggests a link between CNF1 and human inflammatory bowel disease and colorectal cancer. At the cellular level, CNF1 has been hypothesized to reprogram cell fate towards survival due to the role in perturbing cell cycle and apoptosis. However, it remains undetermined how cells survive from CNF1 intoxication. In this work, we show that CNF1 treatment blocks mitosis/cytokinesis, elicits endoreplication and polyploidisation in cultured human colon cancer cells, and drives them into reversible senescence, which provides a survival route for cells via depolyploidisation. Senescence in CNF1-treated cells is demonstrated with upregulation of several senescence markers including senescence-associated β-galactosidase activity, p53, p21 and p16, and concomitant inhibition of the retinoblastoma protein phosphorylation. Importantly, progeny derived from CNF1 treatment exhibit genomic instability exemplified by increased aneuploidy and become more resistant to CNF1, but not to 5-fluorouracil and oxaliplatin, the two agents commonly used in chemotherapeutic treatment for colorectal cancer. These observations display survival features of the cell after CNF1 treatment that may have implications for the potential role of CNF1 in carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

Reversible senescence of human colon cancer cells after blockage of mitosis/cytokinesis caused by the CNF1 cyclomodulin from Escherichia coli

Zhang

Aung

Uhlin

et al. 2018

Sci Rep

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“…The list of natural toxins (i.e., Lerm et al, 2000 ) implicated in Rho GTPase signaling is continuously expanding leading to a great potential that it will provide new avenues for the development of new therapeutics (Maroccia et al, 2018 ).…”

Section: Pharmacological Modulators Of Rho Gtpasesmentioning

confidence: 99%

Pharmacological Modulators of Small GTPases of Rho Family in Neurodegenerative Diseases

Guiler

Koehler

Boykin

et al. 2021

Front. Cell. Neurosci.

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Classical Rho GTPases, including RhoA, Rac1, and Cdc42, are members of the Ras small GTPase superfamily and play essential roles in a variety of cellular functions. Rho GTPase signaling can be turned on and off by specific GEFs and GAPs, respectively. These features empower Rho GTPases and their upstream and downstream modulators as targets for scientific research and therapeutic intervention. Specifically, significant therapeutic potential exists for targeting Rho GTPases in neurodegenerative diseases due to their widespread cellular activity and alterations in neural tissues. This study will explore the roles of Rho GTPases in neurodegenerative diseases with focus on the applications of pharmacological modulators in recent discoveries. There have been exciting developments of small molecules, nonsteroidal anti-inflammatory drugs (NSAIDs), and natural products and toxins for each classical Rho GTPase category. A brief overview of each category followed by examples in their applications will be provided. The literature on their roles in various diseases [e.g., Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic lateral sclerosis (ALS), Frontotemporal dementia (FTD), and Multiple sclerosis (MS)] highlights the unique and broad implications targeting Rho GTPases for potential therapeutic intervention. Clearly, there is increasing knowledge of therapeutic promise from the discovery of pharmacological modulators of Rho GTPases for managing and treating these conditions. The progress is also accompanied by the recognition of complex Rho GTPase modulation where targeting its signaling can improve some aspects of pathogenesis while exacerbating others in the same disease model. Future directions should emphasize the importance of elucidating how different Rho GTPases work in concert and how they produce such widespread yet different cellular responses during neurodegenerative disease progression.

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“…CNFs may also hold promise for treatment of neurological disorders and cancer (Maroccia et al , 2018). For example, CNF1 injection into brains of mice enhanced neurotransmission and synaptic plasticity, leading to improved learning and memory (Diana et al , 2007).…”

Section: Introductionmentioning

confidence: 99%

Crystal structure of bacterial cytotoxic necrotizing factor CNF_Y reveals molecular building blocks for intoxication

et al. 2021

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Cytotoxic necrotizing factors (CNFs) are bacterial single‐chain exotoxins that modulate cytokinetic/oncogenic and inflammatory processes through activation of host cell Rho GTPases. To achieve this, they are secreted, bind surface receptors to induce endocytosis and translocate a catalytic unit into the cytosol to intoxicate host cells. A three‐dimensional structure that provides insight into the underlying mechanisms is still lacking. Here, we determined the crystal structure of full‐length Yersinia pseudotuberculosis CNFY. CNFY consists of five domains (D1–D5), and by integrating structural and functional data, we demonstrate that D1–3 act as export and translocation module for the catalytic unit (D4–5) and for a fused β‐lactamase reporter protein. We further found that D4, which possesses structural similarity to ADP‐ribosyl transferases, but had no equivalent catalytic activity, changed its position to interact extensively with D5 in the crystal structure of the free D4–5 fragment. This liberates D5 from a semi‐blocked conformation in full‐length CNFY, leading to higher deamidation activity. Finally, we identify CNF translocation modules in several uncharacterized fusion proteins, which suggests their usability as a broad‐specificity protein delivery tool.

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New therapeutics from Nature: The odd case of the bacterial cytotoxic necrotizing factor 1

Cited by 11 publications

References 107 publications

Reversible senescence of human colon cancer cells after blockage of mitosis/cytokinesis caused by the CNF1 cyclomodulin from Escherichia coli

Reversible senescence of human colon cancer cells after blockage of mitosis/cytokinesis caused by the CNF1 cyclomodulin from Escherichia coli

Pharmacological Modulators of Small GTPases of Rho Family in Neurodegenerative Diseases

Crystal structure of bacterial cytotoxic necrotizing factor CNF_Y reveals molecular building blocks for intoxication

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New therapeutics from Nature: The odd case of the bacterial cytotoxic necrotizing factor 1

Cited by 11 publications

References 107 publications

Reversible senescence of human colon cancer cells after blockage of mitosis/cytokinesis caused by the CNF1 cyclomodulin from Escherichia coli

Reversible senescence of human colon cancer cells after blockage of mitosis/cytokinesis caused by the CNF1 cyclomodulin from Escherichia coli

Pharmacological Modulators of Small GTPases of Rho Family in Neurodegenerative Diseases

Crystal structure of bacterial cytotoxic necrotizing factor CNFY reveals molecular building blocks for intoxication

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Crystal structure of bacterial cytotoxic necrotizing factor CNF_Y reveals molecular building blocks for intoxication