Involvement of the TRPML Mucolipin Channels in Viral Infections and Anti-viral Innate Immune Responses

Santoni, Giorgio; Morelli, Maria Beatrice; Amantini, Consuelo; Nabissi, Massimo; Santoni, Matteo; Santoni, Angela

doi:10.3389/fimmu.2020.00739

Cited by 25 publications

(21 citation statements)

References 98 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The Mucolipin 2 gene encodes for the transient receptor potential mucolipin channel 2 (TRPML2) protein which belongs to the TRPML family of cation channel proteins ( 89 ). Recent studies have suggested a role for MCOLN2 in the activation of innate immune responses through TLR signaling ( 90 ). This is an interesting correlation given the emerging role for TLR signaling in pSS pathobiology ( 85 , 91 – 93 ).…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic and Network Analysis of Minor Salivary Glands of Patients With Primary Sjögren’s Syndrome

et al. 2021

View full text Add to dashboard Cite

Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized primarily by immune-mediated destruction of exocrine tissues, such as those of the salivary and lacrimal glands, resulting in the loss of saliva and tear production, respectively. This disease predominantly affects middle-aged women, often in an insidious manner with the accumulation of subtle changes in glandular function occurring over many years. Patients commonly suffer from pSS symptoms for years before receiving a diagnosis. Currently, there is no effective cure for pSS and treatment options and targeted therapy approaches are limited due to a lack of our overall understanding of the disease etiology and its underlying pathology. To better elucidate the underlying molecular nature of this disease, we have performed RNA-sequencing to generate a comprehensive global gene expression profile of minor salivary glands from an ethnically diverse cohort of patients with pSS. Gene expression analysis has identified a number of pathways and networks that are relevant in pSS pathogenesis. Moreover, our detailed integrative analysis has revealed a primary Sjögren’s syndrome molecular signature that may represent important players acting as potential drivers of this disease. Finally, we have established that the global transcriptomic changes in pSS are likely to be attributed not only to various immune cell types within the salivary gland but also epithelial cells which are likely playing a contributing role. Overall, our comprehensive studies provide a database-enriched framework and resource for the identification and examination of key pathways, mediators, and new biomarkers important in the pathogenesis of this disease with the long-term goals of facilitating earlier diagnosis of pSS and to mitigate or abrogate the progression of this debilitating disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Transcriptomic and Network Analysis of Minor Salivary Glands of Patients With Primary Sjögren’s Syndrome

et al. 2021

View full text Add to dashboard Cite

show abstract

“…One notable sequence motif in Ls-TRPML is a typical bipartite nuclear localization signal, as with other TRPMLs [33]. We observed that Ls-TRPML-His localized in the nuclear membrane and some aggregated in the nuclei of Sf9 cells (Figure 3A); whether the nucleus entry Ls-TRPML phosphorylated to modulate other proteins functions in L. striatellus needs to be explored further.…”

Section: Discussionmentioning

confidence: 79%

Identification and Characterization Analysis of Transient Receptor Potential Mucolipin Protein of Laodelphax striatellus Fallén

Wang

Dong

Wan³

et al. 2021

Insects

View full text Add to dashboard Cite

Transient receptor potential mucolipin (TRPML) protein in flies plays a pivotal role in Ca2+ ions release, resulting in membrane trafficking, autophagy and ion homeostasis. However, to date, the characterization of TRPML in agricultural pests remains unknown. Here, we firstly reported the TRPML of a destructive pest of gramineous crops, Laodelphax striatellus. The L. striatellus TRPML (Ls-TRPML) has a 1818 bp open reading frame, encoding 605 amino acid. TRPML in agricultural pests is evolutionarily conserved, and the expression of Ls-TRPML is predominately higher in the ovary than in other organs of L. striatellus at the transcript and protein level. The Bac–Bac system showed that Ls-TRPML localized in the plasma membrane, nuclear membrane and nucleus and co-localized with lysosome in Spodoptera frugiperda cells. The immunofluorescence microscopy analysis showed that Ls-TRPML localized in the cytoplasm and around the nuclei of the intestine cells or ovary follicular cells of L. striatellus. The results from the lipid-binding assay revealed that Ls-TRPML strongly bound to phosphatidylinositol-3,5-bisphosphate, as compared with other phosphoinositides. Overall, our results helped is identify and characterize the TRPML protein of L. striatellus, shedding light on the function of TRPML in multiple cellular processes in agricultural pests.

show abstract

“…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%

See 1 more Smart Citation

Peripheral Inflammatory Cytokine Signature Mirrors Motor Deficits in Mucolipidosis IV

Misko

et al. 2021

Preprint

View full text Add to dashboard Cite

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.

show abstract

Involvement of the TRPML Mucolipin Channels in Viral Infections and Anti-viral Innate Immune Responses

Cited by 25 publications

References 98 publications

Transcriptomic and Network Analysis of Minor Salivary Glands of Patients With Primary Sjögren’s Syndrome

Transcriptomic and Network Analysis of Minor Salivary Glands of Patients With Primary Sjögren’s Syndrome

Identification and Characterization Analysis of Transient Receptor Potential Mucolipin Protein of Laodelphax striatellus Fallén

Peripheral Inflammatory Cytokine Signature Mirrors Motor Deficits in Mucolipidosis IV

Contact Info

Product

Resources

About