The Voltage-Gated Hv1 H+ Channel Is Expressed in Tumor-Infiltrating Myeloid-Derived Suppressor Cells

Cozzolino, Marco; Gyöngyösi, Adrienn; Korpos, Éva; Gogolák, Péter; Naseem, Muhammad Umair; Kállai, Judit; Lányi, Árpád; Panyi, György

doi:10.3390/ijms24076216

Cited by 3 publications

(3 citation statements)

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“…It limits our ability to explore genetic and pharmacological approaches that could specifically target Hv1, such as in the case of MDSCs. MDSCs possess the ability to suppress the activation and proliferation of T lymphocytes, and this immunosuppressive function is supported by mHv1 expression and function ( Alvear-Arias, J.J., et al, 2022 ; Cozzolino, M., et al, 2023 ).…”

Section: Discussionmentioning

confidence: 99%

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N-terminal region is responsible for mHv1 channel activity in MDSCs

Peña-Pichicoi,

Fernández,

Navarro-Quezada

et al. 2023

Front. Pharmacol.

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Voltage-gated proton channels (Hv1) are important regulators of the immunosuppressive function of myeloid-derived suppressor cells (MDSCs) in mice and have been proposed as a potential therapeutic target to alleviate dysregulated immunosuppression in tumors. However, till date, there is a lack of evidence regarding the functioning of the Hvcn1 and reports on mHv1 isoform diversity in mice and MDSCs. A computational prediction has suggested that the Hvcn1 gene may express up to six transcript variants, three of which are translated into distinct N-terminal isoforms of mHv1: mHv1.1 (269 aa), mHv1.2 (269 + 42 aa), and mHv1.3 (269 + 4 aa). To validate this prediction, we used RT-PCR on total RNA extracted from MDSCs, and the presence of all six predicted mRNA variances was confirmed. Subsequently, the open-reading frames (ORFs) encoding for mHv1 isoforms were cloned and expressed in Xenopus laevis oocytes for proton current recording using a macro-patch voltage clamp. Our findings reveal that all three isoforms are mammalian mHv1 channels, with distinct differences in their activation properties. Specifically, the longest isoform, mHv1.2, displays a right-shifted conductance–voltage (GV) curve and slower opening kinetics, compared to the mid-length isoform, mHv1.3, and the shortest canonical isoform, mHv1.1. While mHv1.3 exhibits a V0.5 similar to that of mHv1.1, mHv1.3 demonstrates significantly slower activation kinetics than mHv1.1. These results suggest that isoform gating efficiency is inversely related to the length of the N-terminal end. To further explore this, we created the truncated mHv1.2 ΔN20 construct by removing the first 20 amino acids from the N-terminus of mHv1.2. This construct displayed intermediate activation properties, with a V0.5 value lying intermediate of mHv1.1 and mHv1.2, and activation kinetics that were faster than that of mHv1.2 but slower than that of mHv1.1. Overall, these findings indicate that alternative splicing of the N-terminal exon in mRNA transcripts encoding mHv1 isoforms is a regulatory mechanism for mHv1 function within MDSCs. While MDSCs have the capability to translate multiple Hv1 isoforms with varying gating properties, the Hvcn1 gene promotes the dominant expression of mHv1.1, which exhibits the most efficient gating among all mHv1 isoforms.

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Section: Discussionmentioning

confidence: 99%

“…J., et al, 2022). This discovery increases the potential therapeutic value of Hv1, as cancers are known to recruit the MDSC to its microenvironment (Kusmartsev, S., et al, 2008;Corzo, C. A., et al, 2009;Yan, L., et al, 2014;Alvear-Arias, J.J., et al, 2022;Cozzolino, M., et al, 2023;Qin, G., et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

N-terminal region is responsible for mHv1 channel activity in MDSCs

Peña-Pichicoi,

Fernández,

Navarro-Quezada

et al. 2023

Front. Pharmacol.

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“…Subsequently, in response to oxygenation of the Earth's atmosphere, Hv1 channels would have been co-opted for the production of oxygen free radicals, coupled to NADPH oxidase (Okochi et al, 2009). Therefore, I propose that the presence of HV1 channels in myeloid-derived suppressor cells (MDSCs) (Cozzolino, 2022;Cozzolino et al, 2023) also points to the evolutionary origin of the immune system.…”

Section: Evolutionary Remnants Of the Warburg Effect In The Immune Sy...mentioning

confidence: 99%

The first embryo, the origin of cancer and animal phylogeny. IV. The neoplastic basis for the formation of the innate immune system

Cofre

2024

Front. Ecol. Evol.

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The formation of the innate immune system of animals can only be envisioned after the development of the first metazoan embryo. The decisive role of Embryology in understanding the evolution of the immune system has been inexplicably disregarded in the history of science. Some characteristics of our holozoan ancestors, including macrophage-like movement and enteric phagocytosis, were suppressed by the formation of chains of physically attached cells in the context of embryo multicellularity. The formation of the archenteron during morphogenesis of the first embryo resulted in a meta-organism whose survival was dependent on the ability to perform enteric phagocytosis (nutrition on bacteria). By recognizing the neoplastic basis of embryo formation, it is possible to venture a glimpse at its other face, a process that becomes evident when the extracellular matrix and cadherin junctions are destroyed. What ensues is metastasis (in the case of cancer) or an alternative version controlled by cell differentiation (during embryogenesis). In the context of innate immunity, the development of mesogleal cells by epithelial–mesenchymal transition and differentiation into cells specialized in bacterial recognition allowed the newly formed animal to preserve homeostasis, an innovation that has been maintained throughout evolution. In this article, I will share my first reflections on the embryonic origin of innate immunity and its close relationship with cancer. Innate immunity arises naturally during embryogenesis, which explains why the immune system typically does not react against cancer cells. In its essence, the immune system was created from them. Here, I argue that the first embryo can be understood as a benign tumor nourished and protected by the innate immune system.

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