TRP Channels as Interior Designers: Remodeling the Endolysosomal Compartment in Natural Killer Cells

Clement, Dennis; Goodridge, Jodie P.; Patel, Sandip; Malmberg, Karl‐Johan

doi:10.3389/fimmu.2020.00753

Cited by 15 publications

(13 citation statements)

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“…Probably, mitochondrial ROS can regulate exocytosis of mast cells by acting on Ca 2+ channels in secretory granules. The main lysosomal Ca 2+ channel mucolipin-1 (MCOLN1/TRPML1) is localized in the secretory lysosomes of NK cells related to secretory granules ( 73 ) and can be directly activated by mitochondrial ROS ( 61 , 74 , 75 ). Ca 2+ release via TRPML1 leads to lysosomal fission ( 76 ) and calcineurin-dependent translocation of the nuclear transcription factor TFEB which stimulates lysosome exocytosis, autophagy, and lysosome biogenesis ( 61 , 74 , 75 ).…”

Section: The Role Played By Mitochondria In the Fcεri-dependent Mast mentioning

confidence: 99%

The Role Played by Mitochondria in FcεRI-Dependent Mast Cell Activation

et al. 2020

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Mast cells play a key role in the regulation of innate and adaptive immunity and are involved in pathogenesis of many inflammatory and allergic diseases. The most studied mechanism of mast cell activation is mediated by the interaction of antigens with immunoglobulin E (IgE) and a subsequent binding with the high-affinity receptor Fc epsilon RI (FcεRI). Increasing evidences indicated that mitochondria are actively involved in the FcεRI-dependent activation of this type of cells. Here, we discuss changes in energy metabolism and mitochondrial dynamics during IgE-antigen stimulation of mast cells. We reviewed the recent data with regards to the role played by mitochondrial membrane potential, mitochondrial calcium ions (Ca 2+) influx and reactive oxygen species (ROS) in mast cell FcεRI-dependent activation. Additionally, in the present review we have discussed the crucial role played by the pyruvate dehydrogenase (PDH) complex, transcription factors signal transducer and activator of transcription 3 (STAT3) and microphthalmia-associated transcription factor (MITF) in the development and function of mast cells. These two transcription factors besides their nuclear localization were also found to translocate in to the mitochondria and functions as direct modulators of mitochondrial activity. Studying the role played by mast cell mitochondria following their activation is essential for expanding our basic knowledge about mast cell physiological functions and would help to design mitochondria-targeted anti-allergic and anti-inflammatory drugs.

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Section: The Role Played By Mitochondria In the Fcεri-dependent Mast mentioning

confidence: 99%

The Role Played by Mitochondria in FcεRI-Dependent Mast Cell Activation

et al. 2020

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“…TRPML1 has a well-established role in regulating a broad range of lysosomal functions (Colletti & Kiselyov, 2011; Di Paola, Scotto-Rosato, & Medina, 2018; Huang, Xu, Wu, Rizvi Syeda, & Dong, 2020; Wang, Zhang, Gao, & Xu, 2014) and recent data suggest its role in immune cell function (Bretou et al, 2017; Clement, Goodridge, Grimm, Patel, & Malmberg, 2020; Dayam, Saric, Shilliday, & Botelho, 2015; Goodridge et al, 2019; Santoni et al, 2020). TRPML1 activity promotes nuclear translocation of transcriptional factor EB (TFEB) (Medina et al, 2015), resulting in activation of the CLEAR network of genes, which include lysosomal hydrolases, genes of lysosomal biogenesis and autophagy (Palmieri et al, 2011; Settembre & Medina, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the TRPML1-TFEB regulatory loop may play a central role in the transcriptional regulation of immune cells. TRPML1 has also been shown to play a role in macrophage phagophore formation, migration of dendritic cells and regulation of the effector activity of natural-killer cells Bretou et al, 2017; Clement, Goodridge, Grimm, Patel, & Malmberg, 2020; Dayam, Saric, Shilliday, & Botelho, 2015; Goodridge et al, 2019; Santoni et al, 2020). Additionally, loss of TRPML1 leads to pro-inflammatory activation of microglia and a disease-associated transcriptomic signature in the MLIV mouse microglia (Cougnoux et al, 2019), although functional consequences of these changes and role of microglia in the pathophysiology of MLIV are still not fully understood.…”

Section: Discussionmentioning

confidence: 99%

“…Though several studies demonstrate the role of TRPML1 in regulating immune cell functions in in vitro systems (Bretou et al, 2017; Clement et al, 2020; Dayam et al, 2015; Goodridge et al, 2019; Santoni et al, 2020), no peripheral immune-related clinical manifestations have yet been documented in MLIV patients. The reason for the lack of immune symptoms can be explained by compensatory mechanisms in immune system, potentially via an TRPML1 ortholog, TRPML2.…”

Section: Discussionmentioning

confidence: 99%

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Peripheral Inflammatory Cytokine Signature Mirrors Motor Deficits in Mucolipidosis IV

Misko

et al. 2021

Preprint

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Mucolipidosis IV (MLIV) is an autosomal-recessive pediatric disease that leads to motor and cognitive deficits and loss of vision. It is caused by loss-of-function of the lysosomal channel transient receptor potential mucolipin-1 and is associated with an early pro-inflammatory brain phenotype, including increased cytokine expression. We thus hypothesized that peripheral blood cytokines would reflect inflammatory changes in the brain and would be linked to motor dysfunction. To test this, we collected plasma from MLIV patients and parental controls concomitantly with assessment of motor function using the Brief Assessment of Motor Function and Modified Ashworth scores. We found that MLIV patients had prominently increased cytokine levels compared to familial controls and identified profiles of cytokines correlated with motor dysfunction, including IFN-γ, IFN-α2, IL-17, IP-10. We found that IP-10 was a key differentiating factor separating MLIV cases from controls based on data from human plasma, mouse plasma, and mouse brain. Like MLIV patients, IL-17 and IP-10 were up-regulated in blood of symptomatic mice. Together, our data indicate that MLIV is characterized by increased blood cytokines, which are strongly related to underlying neurological and functional deficits in MLIV patients. Moreover, our data identify the interferon pro-inflammatory axis in both human and mouse signatures, suggesting an importance for interferon signaling in MLIV.

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“…TRPML channels (TRPML1-3) are Ca 2+ permeable cation channels that each contain six transmembrane segments with helices (S1–S6) and a pore site comprised of S5, S6, and two pore helices (PH1 and PH2) (Schmiege et al, 2018 ; Tedeschi et al, 2019 ). TRPML channels are mostly located in intracellular compartments instead of the plasma membrane (Clement et al, 2020 ). TRPP channels share high protein sequence similarity with TRPML channels and are located in the primary cilia consisting of TRPP1 (also known as PKD1) and TRPP2 (PKD2) (Samanta et al, 2018 ).…”

Section: Brain Disordersmentioning

confidence: 99%

The Role of TRP Channels and PMCA in Brain Disorders: Intracellular Calcium and pH Homeostasis

Hwang

Lee

Kim

2021

Front. Cell Dev. Biol.

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Brain disorders include neurodegenerative diseases (NDs) with different conditions that primarily affect the neurons and glia in the brain. However, the risk factors and pathophysiological mechanisms of NDs have not been fully elucidated. Homeostasis of intracellular Ca2+ concentration and intracellular pH (pHi) is crucial for cell function. The regulatory processes of these ionic mechanisms may be absent or excessive in pathological conditions, leading to a loss of cell death in distinct regions of ND patients. Herein, we review the potential involvement of transient receptor potential (TRP) channels in NDs, where disrupted Ca2+ homeostasis leads to cell death. The capability of TRP channels to restore or excite the cell through Ca2+ regulation depending on the level of plasma membrane Ca2+ ATPase (PMCA) activity is discussed in detail. As PMCA simultaneously affects intracellular Ca2+ regulation as well as pHi, TRP channels and PMCA thus play vital roles in modulating ionic homeostasis in various cell types or specific regions of the brain where the TRP channels and PMCA are expressed. For this reason, the dysfunction of TRP channels and/or PMCA under pathological conditions disrupts neuronal homeostasis due to abnormal Ca2+ and pH levels in the brain, resulting in various NDs. This review addresses the function of TRP channels and PMCA in controlling intracellular Ca2+ and pH, which may provide novel targets for treating NDs.

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TRP Channels as Interior Designers: Remodeling the Endolysosomal Compartment in Natural Killer Cells

Cited by 15 publications

References 183 publications

The Role Played by Mitochondria in FcεRI-Dependent Mast Cell Activation

The Role Played by Mitochondria in FcεRI-Dependent Mast Cell Activation

Peripheral Inflammatory Cytokine Signature Mirrors Motor Deficits in Mucolipidosis IV

The Role of TRP Channels and PMCA in Brain Disorders: Intracellular Calcium and pH Homeostasis

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