Table of contents

Volume 10, Issue 6, pp. 117 - 140, June 2023

Issue cover
Cover: Colorized transmission electron micrograph of an HIV-1 virus particle (red/yellow) budding from the plasma membrane of an infected H9 T cell (blue). Image by the National Institute of Allergy and Infectious Diseases (NIAID), USA, captured at the NIAID Integrated Research Facility in Fort Detrick, Maryland, USA; image modified by MIC. The cover is published under the Creative Commons Attribution (CC BY) license. Enlarge issue cover

Research Articles

TL-532, a novel specific Toll-like receptor 3 agonist rationally designed for targeting cancers: discovery process and biological characterization

Sylvain Thierry, Sarah Maadadi, Aurore Berton, Laura Dimier, Clémence Perret, Nelly Vey, Saïd Ourfali, Mathilde Saccas, Solène Caron, Mathilde Boucard-Jourdin, Marc Colombel, Bettina Werle and Marc Bonnin

page 117-132 | 10.15698/mic2023.06.797 | Full text | PDF | Abstract

Toll-like receptor 3 (TLR3) is an innate immune receptor that recognizes double-stranded RNA (dsRNA) and induces inflammation in immune and normal cells to initiate anti-microbial responses. TLR3 acts also as a death receptor only in cancer cells but not in their normal counterparts, making it an attractive target for cancer therapies. To date, all of the TLR3-activating dsRNAs used at preclinical or clinical stages have major drawbacks such as structural heterogeneity, toxicity, and lack of specificity and/or efficacy. We conducted the discovery process of a new family of TLR3 agonists that are chemically manufactured on solid-phase support and perfectly defined in terms of sequence and size. A stepwise discovery process was performed leading to the identification of TL-532, a 70 base pair dsRNA that is potent without transfection reagent and is highly specific for TLR3 without activating other innate nucleic sensors such as RIG-I/MDA5, TLR7, TLR8, and TLR9. TL-532 induces inflammation in murine RAW264.7 myeloid macrophages, in human NCI-H292 lung cancer cells, and it promotes immunogenic apoptosis in tumor cells in vitro and ex vivo without toxicity towards normal primary cells. In conclusion, we identified a novel TLR3 agonist called TL-532 that has promising anticancer properties.

Research Reports

Atg1, a key regulator of autophagy, functions to promote MAPK activation and cell death upon calcium overload in fission yeast

Teruaki Takasaki, Ryosuke Utsumi, Erika Shimada, Asuka Bamba, Kanako Hagihara, Ryosuke Satoh, and Reiko Sugiura

page 133-140 | 10.15698/mic2023.06.798 | Full text | PDF | Abstract

Autophagy promotes or inhibits cell death depending on the environment and cell type. Our previous findings suggested that Atg1 is genetically involved in the regula-tion of Pmk1 MAPK in fission yeast. Here, we showed that Δatg1 displays lower levels of Pmk1 MAPK phosphorylation than did the wild-type (WT) cells upon treatment with a 1,3-β-D-glucan synthase inhibitor micafungin or CaCl2, both of which activate Pmk1. Moreover, the overproduction of Atg1, but not that of the kinase inactivating Atg1D193A activates Pmk1 without any extracellular stimuli, suggesting that Atg1 may promote Pmk1 MAPK signaling activation. Notably, the overproduction of Atg1 induces a toxic effect on the growth of WT cells and the deletion of Pmk1 failed to suppress the cell death induced by Atg1, indicating that the Atg1-mediated cell death requires additional mechanism(s) other than Pmk1 activation. Moreover, atg1 gene deletion induces tolerance to micafungin and CaCl2, whereas pmk1 deletion induces severe sensitivities to these compounds. The Δatg1Δpmk1 double mutants display intermediate sensitivities to these compounds, showing that atg1 deletion partly suppressed growth inhibition induced by Δpmk1. Thus, Atg1 may act to promote cell death upon micafungin and CaCl2 stimuli regardless of Pmk1 MAPK activity. Since micafungin and CaCl2 are intracellular calcium inducers, our data reveal a novel role of the autophagy regulator Atg1 to induce cell death upon calcium overload independent of its role in Pmk1 MAPK activation.

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