Multiple facets of TRPML1 in autophagy

Huang, Peng; Xu, Mengnan; Wu, Yi; Syeda, Alia Kazim Rizvi; Dong, Xian‐Ping

doi:10.1016/j.ceca.2020.102196

Cited by 20 publications

(18 citation statements)

References 9 publications

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“…These channels have not been explored in the context of lung disease yet but may be interesting candidates for relevant roles in lung physiology and pathophysiology such as TRPML3. Their roles in autophagy [ 48 , 49 , 50 , 51 , 52 ], release of inflammatory mediators [ 53 , 54 , 55 ], endolysosomal trafficking, exocytosis and phagocytosis [ 56 , 57 , 58 , 59 , 60 , 61 ], and their presence in the lung highly suggest functional relevant roles in lung diseases.…”

Section: Discussionmentioning

confidence: 99%

Endolysosomal Cation Channels and Lung Disease

Spix

Jeridi

Ansari

et al. 2022

Cells

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Endolysosomal cation channels are emerging as key players of endolysosomal function such as endolysosomal trafficking, fusion/fission, lysosomal pH regulation, autophagy, lysosomal exocytosis, and endocytosis. Diseases comprise lysosomal storage disorders (LSDs) and neurodegenerative diseases, metabolic diseases, pigmentation defects, cancer, immune disorders, autophagy related diseases, infectious diseases and many more. Involvement in lung diseases has not been a focus of attention so far but recent developments in the field suggest critical functions in lung physiology and pathophysiology. Thus, loss of TRPML3 was discovered to exacerbate emphysema formation and cigarette smoke induced COPD due to dysregulated matrix metalloproteinase 12 (MMP-12) levels in the extracellular matrix of the lung, a known risk factor for emphysema/COPD. While direct lung function measurements with the exception of TRPML3 are missing for other endolysosomal cation channels or channels expressed in lysosome related organelles (LRO) in the lung, links between those channels and important roles in lung physiology have been established such as the role of P2X4 in surfactant release from alveolar epithelial Type II cells. Other channels with demonstrated functions and disease relevance in the lung such as TRPM2, TRPV2, or TRPA1 may mediate their effects due to plasma membrane expression but evidence accumulates that these channels might also be expressed in endolysosomes, suggesting additional and/or dual roles of these channels in cell and intracellular membranes. We will discuss here the current knowledge on cation channels residing in endolysosomes or LROs with respect to their emerging roles in lung disease.

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Section: Discussionmentioning

confidence: 99%

Endolysosomal Cation Channels and Lung Disease

Spix

Jeridi

Ansari

et al. 2022

Cells

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“…TRPML1 has a well-established role in regulating a broad range of lysosomal functions [29,30], and recent data suggest its role in immune cell function [31][32][33][34][35]. TRPML1 activity promotes nuclear translocation of transcriptional factor EB (TFEB) [36], resulting in the activation of the CLEAR network of genes, which include lysosomal hydrolases, genes of lysosomal biogenesis, and autophagy [37,38].…”

Section: Discussionmentioning

confidence: 99%

Peripheral Inflammatory Cytokine Signature Mirrors Motor Deficits in Mucolipidosis IV

Misko

Weinstock

Sankar

et al. 2022

Cells

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Background: Mucolipidosis IV (MLIV) is an autosomal recessive pediatric disease that leads to motor and cognitive deficits and loss of vision. It is caused by a 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. The goal of the current study was to determine whether blood cytokines are linked to motor dysfunction in patients with MLIV and reflect brain inflammatory changes observed in an MLIV mouse model. Methods: To determine the relationship between blood cytokines and motor function, 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 scales. We then compared these profiles with cytokine profiles in brain and plasma samples collected from the Mcoln1−/− mouse model of MLIV. Results: 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, and 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. Conclusions: 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 that interferon signaling is an important aspect of MLIV pathology.

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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%

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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Multiple facets of TRPML1 in autophagy

Cited by 20 publications

References 9 publications

Endolysosomal Cation Channels and Lung Disease

Endolysosomal Cation Channels and Lung Disease

Peripheral Inflammatory Cytokine Signature Mirrors Motor Deficits in Mucolipidosis IV

Peripheral Inflammatory Cytokine Signature Mirrors Motor Deficits in Mucolipidosis IV

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