Identification of TMEM206 proteins as pore of PAORAC/ASOR acid-sensitive chloride channels

Ullrich, Florian; Blin, Sandy; Lazarow, Katina; Daubitz, Tony; Kries, Jens Peter von; Jentsch, Thomas J.

doi:10.7554/elife.49187

Cited by 75 publications

(171 citation statements)

References 59 publications

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“…A previous study has reported that the TMEM family is widely expressed in mammalian cells (39), which is in accordance with the present study. In the present study, the results of the expression profiling analysis demonstrated that TMEM206 expression was significantly increased in colorectal cancer, breast cancer, lymphoma and liver cancer, and reduced in the kidney cancer datasets.…”

Section: Discussionsupporting

confidence: 94%

TMEM206 is a potential prognostic marker of hepatocellular carcinoma

et al. 2020

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Transmembrane proteins are involved in the transportation of materials into and out of cells. The transmembrane protein (TMEM) family is a collection of poorly described transmembrane proteins that serve important roles in tumor development and progression. A number of TMEM proteins have been discovered. A newly discovered TMEM protein, TMEM206, transports ions across the membrane under physiological and pathological conditions, generating an acidic environment, which serves an important role in the microenvironment. However, the prognostic value and regulatory mechanisms of action of TMEM206 in tumors is unclear. The aim of the present study was to evaluate the prognostic value and regulation mechanisms of TMEM206 in tumors. Firstly, the expression of TMEM206 in tumors and normal tissues was assessed using the GEPIA and Oncomine databases and the results revealed that TMEM206 expression increased or decreased depending on the type of tumor. Subsequently, using the Human Protein Atlas and the Kaplan-Meier plotter, the findings of the present study revealed that TMEM206 is related to the prognosis of hepatocellular carcinoma. In order to explore the mechanism of TMEM206 in promoting tumor progression, GEO and cBioPortal were used to determine genes that may be co-expressed with TMEM206. MetaScape was used to identify the signaling pathways that TMEM206 may participate in. Finally, miRWalk, miRDB and TargetScan were used to identify miRNAs that may regulate the expression of TMEM206 and the findings revealed that 2 miRNA (hsa-miR-325 and hsa-miR-510-5p) were involved. In conclusion, upregulation of TMEM206 is associated with poor prognosis in patients with hepatocellular carcinoma.

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Section: Discussionsupporting

confidence: 94%

TMEM206 is a potential prognostic marker of hepatocellular carcinoma

et al. 2020

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“…activated Cl − channel (PAC or PACC1, Fig. 1A), in two independent screens (Ullrich et al, 2019;Yang et al, 2019a). PAC is involved in acid-induced neuronal cell death and PACknockout mice are partially protected from ischemic brain injury (Yang et al, 2019a).…”

Section: Acidosismentioning

confidence: 99%

“…Identifying and characterizing these channels has relied heavily on fluorescent chloride reporters. In many cases, screens using genetically encoded halide-sensitive yellow fluorescent protein (YFP) variants have identified the chloride channel involved in a given physiological process (Ullrich et al, 2019;Voss et al, 2014, Qiu et al, 2014Yang et al, 2019a). However, diverse physiological roles for chloride necessitate reporters that can provide information in various contexts.…”

Section: Introductionmentioning

confidence: 99%

What biologists want from their chloride reporters – a conversation between chemists and biologists

Zajac

Chakraborty

Saha

et al. 2020

Journal of Cell Science

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Impaired chloride transport affects diverse processes ranging from neuron excitability to water secretion, which underlie epilepsy and cystic fibrosis, respectively. The ability to image chloride fluxes with fluorescent probes has been essential for the investigation of the roles of chloride channels and transporters in health and disease. Therefore, developing effective fluorescent chloride reporters is critical to characterizing chloride transporters and discovering new ones. However, each chloride channel or transporter has a unique functional context that demands a suite of chloride probes with appropriate sensing characteristics. This Review seeks to juxtapose the biology of chloride transport with the chemistries underlying chloride sensors by exploring the various biological roles of chloride and highlighting the insights delivered by studies using chloride reporters. We then delineate the evolution of small-molecule sensors and genetically encoded chloride reporters. Finally, we analyze discussions with chloride biologists to identify the advantages and limitations of sensors in each biological context, as well as to recognize the key design challenges that must be overcome for developing the next generation of chloride sensors.

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“…Further studies on the ion channel properties of human PAC with point mutations and fish PAC suggested that PAC directly forms the proton-activated Cl − channel pore [6]. Using a very similar approach, another independent study also identified PAC (TMEM206) as the proton-activated Cl − channel [7].…”

Section: Introductionmentioning

confidence: 95%

PAC proton-activated chloride channel contributes to acid-induced cell death in primary rat cortical neurons

et al. 2020

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Severe local acidosis causes tissue damage and pain, and is associated with many diseases, including cerebral and cardiac ischemia, cancer, infection, and inflammation. However, the molecular mechanisms of the cellular response to extracellular acidic environment are not fully understood. We recently identified a novel and evolutionarily conserved membrane protein, PAC (also known as PACC1 or TMEM206), encoding the proton-activated chloride (Cl −) channel, whose activity is widely observed in human cell lines. We demonstrated that genetic deletion of Pac abolished the proton-activated Cl − currents in mouse neurons and also attenuated the acid-induced neuronal cell death and brain damage after ischemic stroke. Here, we show that the proton-activated Cl − currents are also conserved in primary rat cortical neurons, with characteristics similar to those observed in human and mouse cells. Pac gene knockdown nearly abolished the proton-activated Cl − currents in rat neurons and reduced the neuronal cell death triggered by acid treatment. These data further support the notion that activation of the PAC channel and subsequent Cl − entry into neurons during acidosis play a pathogenic role in acidotoxicity and brain injury.

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Identification of TMEM206 proteins as pore of PAORAC/ASOR acid-sensitive chloride channels

Cited by 75 publications

References 59 publications

TMEM206 is a potential prognostic marker of hepatocellular carcinoma

TMEM206 is a potential prognostic marker of hepatocellular carcinoma

What biologists want from their chloride reporters – a conversation between chemists and biologists

PAC proton-activated chloride channel contributes to acid-induced cell death in primary rat cortical neurons

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