The ion channel TRPV1 gain-of-function reprograms the immune microenvironment to facilitate colorectal tumorigenesis

Malaria caused by the apicomplexan parasite Plasmodium falciparum has served as a strong evolutionary force throughout human history, selecting for red blood cell polymorphisms that confer innate protection against severe disease. Recently, gain-of-function mutations in the mechanosensitive ion channel PIEZO1 were shown to ameliorate Plasmodium parasite growth, blood–brain barrier dysfunction, and mortality in a mouse model of malaria. In humans, the gain-of-function allele PIEZO1 E756del is highly prevalent and enriched in Africans, raising the possibility that it is under positive selection due to malaria. Here we used a case-control study design to test for an association between PIEZO1 E756del and malaria severity among children in Gabon. We found that the E756del variant is strongly associated with protection against severe malaria in heterozygotes. In subjects with sickle cell trait, heterozygosity for PIEZO1 E756del did not confer additive protection and homozygosity was associated with an elevated risk of severe disease, suggesting an epistatic relationship between hemoglobin S and PIEZO1 E756del. Using donor blood samples, we show that red cells heterozygous for PIEZO1 E756del are not dehydrated and can support the intracellular growth of P. falciparum similar to wild-type cells. However, surface expression of the P. falciparum virulence protein PfEMP-1 was significantly reduced in infected cells heterozygous for PIEZO1 756del, a phenomenon that has been observed with other protective polymorphisms, such as hemoglobin C. Our findings demonstrate that PIEZO1 is an important innate determinant of malaria susceptibility in humans and suggest that the mechanism of protection may be related to impaired export of P. falciparum virulence proteins.

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TIAM2S Mediates Serotonin Homeostasis and Provokes a Pro-Inflammatory Immune Microenvironment Permissive for Colorectal Tumorigenesis

Cancers ◽

10.3390/cancers12071844 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1844 ◽

Cited By ~ 1

Author(s):

Ya-Ling Chan ◽

Wei-Chung Lai ◽

Jia-Shing Chen ◽

Joseph Ta-Chien Tseng ◽

Pei-Chin Chuang ◽

...

Keyword(s):

T Lymphocytes ◽

Tumor Development ◽

Lymphocytic Infiltration ◽

Serotonin Level ◽

Inflammation Marker ◽

Immunomodulatory Effects ◽

Immune Microenvironment ◽

Colorectal Tumorigenesis ◽

Colonic Lesion ◽

Proliferation And Invasion

The short isoform of human TIAM2 has been shown to promote proliferation and invasion in various cancer cells. However, the roles of TIAM2S in immune cells in relation to tumor development have not been investigated. To characterize the effects of TIAM2S, we generated TIAM2S-overexpressing mouse lines and found that aged TIAM2S-transgenic (TIAM2S-TG) developed significantly higher occurrence of lymphocytic infiltration and tumorigenesis in various organs, including colon. In addition, TIAM2S-TG is more sensitized to AOM-induced colon tumor development, suggesting a priming effect toward tumorigenesis. In the light of our recent findings that TIAM2S functions as a novel regulator of cellular serotonin level, we found that serotonin, in addition to Cox2, is a unique inflammation marker presented in the colonic lesion sites in the aged TG animals. Furthermore, our results demonstrated that ectopic TIAM2S altered immunity via the expansion of T lymphocytes; this was especially pronounced in CD8+ T cells in combination with CXCL13/BCA-1 pro-inflammatory chemokine in the serum of TIAM2S-TG mice. Consequently, T lymphocytes and B cells were recruited to the lesion sites and stimulated IL-23/IL17A expression to form the tertiary lymphoid organs. Collectively, our research suggests that TIAM2S provokes a pro-inflammatory immune microenvironment permissive to colorectal tumorigenesis through the serotonin-induced immunomodulatory effects.

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Gain of Function of Ion Channel TRPV1 Exacerbates Experimental Colitis by Promoting Dendritic Cell Activation

Molecular Therapy — Nucleic Acids ◽

10.1016/j.omtn.2020.10.006 ◽

2020 ◽

Vol 22 ◽

pp. 924-936

Author(s):

Lina Duo ◽

Ting Wu ◽

Ziliang Ke ◽

Linghan Hu ◽

Chaohui Wang ◽

...

Keyword(s):

Dendritic Cell ◽

Ion Channel ◽

Cell Activation ◽

Experimental Colitis ◽

Dendritic Cell Activation ◽

Gain Of Function

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Age-Associated Ion Channel Localization and Expression Changes Regulate Cardiac Sodium Gain-of-Function

Biophysical Journal ◽

10.1016/j.bpj.2020.11.2092 ◽

2021 ◽

Vol 120 (3) ◽

pp. 333a

Author(s):

Madison B. Nowak ◽

Steven Poelzing ◽

Seth H. Weinberg

Keyword(s):

Ion Channel ◽

Gain Of Function

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A common polymorphism in the druggable ion channel PIEZO1 is associated with protection from severe malaria

10.1101/691253 ◽

2019 ◽

Cited By ~ 1

Author(s):

Christian N. Nguetse ◽

Natasha Purington ◽

Bikash Shakya ◽

Emily R. Ebel ◽

Peter G. Kremsner ◽

...

Keyword(s):

Ion Channel ◽

Red Blood Cells ◽

Severe Malaria ◽

Blood Cells ◽

Sickle Cell Trait ◽

Antimalarial Activity ◽

Severe Disease ◽

Parasite Growth ◽

Barrier Dysfunction ◽

Gain Of Function

AbstractMalaria caused by the Apicomplexan parasite Plasmodium falciparum has served as a strong evolutionary force throughout human history, selecting for red blood cell polymorphisms that confer innate protection against severe disease. Recently, gain-of-function mutations in the mechanosensitive ion channel PIEZO1 were shown to ameliorate Plasmodium parasite growth, blood-brain barrier dysfunction, and mortality in a mouse model of malaria. In humans, the gain-of-function allele PIEZO1 E756del is highly prevalent and enriched in Africans, raising the possibility that it is under positive selection due to malaria. Here we used a case-control study design to test for an association between PIEZO1 E756del and malaria severity among children in Gabon. We found that the E756del variant is strongly associated with protection against severe malaria in heterozygotes, independent of the protection conferred by the sickle cell trait (hemoglobin AS). In vitro experiments using donor red blood cells failed to find an effect of E756del on parasite growth, suggesting this variant confers a mild channel defect and/or that its protective effect may be mediated by other tissue types in vivo. Nonetheless, we show that Yoda1, a small molecule agonist of PIEZO1, has potent antimalarial activity in both E756del and wild-type red blood cells. Our findings demonstrate that PIEZO1 is an important innate determinant of malaria susceptibility in humans and holds potential as druggable host target for malaria control.

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Function and regulation of TRPP2 ion channel revealed by a gain-of-function mutant

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1517066113 ◽

2016 ◽

Vol 113 (17) ◽

pp. E2363-E2372 ◽

Cited By ~ 31

Author(s):

Mahmud Arif Pavel ◽

Caixia Lv ◽

Courtney Ng ◽

Lei Yang ◽

Parul Kashyap ◽

...

Keyword(s):

Ion Channel ◽

Transient Receptor Potential ◽

Transmembrane Domain ◽

Single Point ◽

Receptor Potential ◽

Cyst Formation ◽

Activation Mechanism ◽

Gain Of Function ◽

Monovalent Ions

Mutations in polycystin-1 and transient receptor potential polycystin 2 (TRPP2) account for almost all clinically identified cases of autosomal dominant polycystic kidney disease (ADPKD), one of the most common human genetic diseases. TRPP2 functions as a cation channel in its homomeric complex and in the TRPP2/polycystin-1 receptor/ion channel complex. The activation mechanism of TRPP2 is unknown, which significantly limits the study of its function and regulation. Here, we generated a constitutively active gain-of-function (GOF) mutant of TRPP2 by applying a mutagenesis scan on the S4–S5 linker and the S5 transmembrane domain, and studied functional properties of the GOF TRPP2 channel. We found that extracellular divalent ions, including Ca2+, inhibit the permeation of monovalent ions by directly blocking the TRPP2 channel pore. We also found that D643, a negatively charged amino acid in the pore, is crucial for channel permeability. By introducing single-point ADPKD pathogenic mutations into the GOF TRPP2, we showed that different mutations could have completely different effects on channel activity. The in vivo function of the GOF TRPP2 was investigated in zebrafish embryos. The results indicate that, compared with wild type (WT), GOF TRPP2 more efficiently rescued morphological abnormalities, including curly tail and cyst formation in the pronephric kidney, caused by down-regulation of endogenous TRPP2 expression. Thus, we established a GOF TRPP2 channel that can serve as a powerful tool for studying the function and regulation of TRPP2. The GOF channel may also have potential application for developing new therapeutic strategies for ADPKD.

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