Flotillin-1 Interacts With and Sustains the Surface Levels of TRPV2 Channel

Hu, Juan; Gao, Yue; Huang, Qian; Wang, Yuanyuan; Mo, Xiaoyi; Wang, Peiyu; Zhang, Youjing; Xie, Chang; Li, Dongdong; Yao, Jing

doi:10.3389/fcell.2021.634160

Cited by 8 publications

(7 citation statements)

References 60 publications

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“…As previously described, the two-hybrid yeast screen was conducted using the Matchmaker GAL4-based two-hybrid system (Clontech) [55]. ELMOD3 prey vectors with Flotillin2 or Rab1A bait vectors in different combinations were co-transformed into yeast strain AH109.…”

Section: Methodsmentioning

confidence: 99%

ELMOD3-Rab1A-Flotillin2 cascade regulates lumen formation via vesicle trafficking inCionanotochord

et al. 2023

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Lumen development is a crucial phase in tubulogenesis, although its molecular mechanisms are largely unknown. In this study, we discovered an ELMO domain-containing 3 (ELMOD3), which belongs to ADP-ribosylation factor GTPase-activating protein family, was necessary to form the notochord lumen in Ciona larvae . We demonstrated that ELMOD3 interacted with lipid raft protein Flotillin2 and regulated its subcellular localization. The loss-of-function of Flotillin2 prevented notochord lumen formation. Furthermore, we found that ELMOD3 also interacted with Rab1A, which is the regulatory GTPase for vesicle trafficking and located at the notochord cell surface. Rab1A mutations arrested the lumen formation, phenocopying the loss-of-function of ELMOD3 and Flotillin2. Our findings further suggested that Rab1A interactions influenced Flotillin2 localization. We thus identified a unique pathway in which ELMOD3 interacted with Rab1A, which controlled the Flotillin2-mediated vesicle trafficking from cytoplasm to apical membrane, required for Ciona notochord lumen formation.

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Section: Methodsmentioning

confidence: 99%

ELMOD3-Rab1A-Flotillin2 cascade regulates lumen formation via vesicle trafficking inCionanotochord

et al. 2023

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“…Furthermore, immunofluorescence studies revealed that FLOT1 and GPRC5A-GFP were both concentrated at the cell periphery in membrane-associated microdomains reminiscent of lipid rafts in both replication states, with enhanced co-localisation observed during lytic replication ( Figure 5 D). Previous studies have suggested that flotillins modulate the activity of several membrane proteins by enhancing their surface expression [ 61 ]. As GPCRs are commonly associated with cellular signalling pathways, we hypothesise that improved organisation of GPRC5A into these membrane-associated microdomains during lytic replication may allow for increased signal transduction through this protein [ 62 ].…”

Section: Resultsmentioning

confidence: 99%

m6A Regulates the Stability of Cellular Transcripts Required for Efficient KSHV Lytic Replication

Manners

Baquero-Pérez

Mottram

et al. 2023

Viruses

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The epitranscriptomic modification N6-methyladenosine (m6A) is a ubiquitous feature of the mammalian transcriptome. It modulates mRNA fate and dynamics to exert regulatory control over numerous cellular processes and disease pathways, including viral infection. Kaposi’s sarcoma-associated herpesvirus (KSHV) reactivation from the latent phase leads to the redistribution of m6A topology upon both viral and cellular mRNAs within infected cells. Here we investigate the role of m6A in cellular transcripts upregulated during KSHV lytic replication. Our results show that m6A is crucial for the stability of the GPRC5A mRNA, whose expression is induced by the KSHV latent–lytic switch master regulator, the replication and transcription activator (RTA) protein. Moreover, we demonstrate that GPRC5A is essential for efficient KSHV lytic replication by directly regulating NFκB signalling. Overall, this work highlights the central importance of m6A in modulating cellular gene expression to influence viral infection.

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“…FLOT1 is known to influence several cellular processes, such as gene expression, receptor internalization into the cellular membrane, and T-cell activation [ 25 , 65 ]. Further, it was shown that FLOT1 interacts with TRPV2 channels and regulates its function in murine DRG neurons [ 66 ]. We demonstrated that old GLA KO DRG neurons show a higher number of FLOT1 + neurons with a membranous distribution pattern compared to young WT and GLA KO, and old WT mice ( Figure 7 ), which might hint towards impaired internalization processes and trafficking of pain-associated ion channels such as KCa3.1 and TRPA1.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of Immune Response Mediators and Pain-Related Ion Channels Is Associated with Pain-like Behavior in the GLA KO Mouse Model of Fabry Disease

Spitzel

Wagner

Breyer

et al. 2022

Cells

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Fabry disease (FD) is a rare life-threatening disorder caused by deficiency of the alpha-galactosidase A (GLA) enzyme with a characteristic pain phenotype. Impaired GLA production or function leads to the accumulation of the cell membrane compound globotriaosylceramide (Gb3) in the neurons of the dorsal root ganglia (DRG) of FD patients. Applying immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT PCR) analysis on DRG tissue of the GLA knockout (KO) mouse model of FD, we address the question of how Gb3 accumulation may contribute to FD pain and focus on the immune system and pain-associated ion channel gene expression. We show a higher Gb3 load in the DRG of young (<6 months) (p < 0.01) and old (≥12 months) (p < 0.001) GLA KO mice compared to old wildtype (WT) littermates, and an overall suppressed immune response in the DRG of old GLA KO mice, represented by a reduced number of CD206+ macrophages (p < 0.01) and lower gene expression levels of the inflammation-associated targets interleukin(IL)1b (p < 0.05), IL10 (p < 0.001), glial fibrillary acidic protein (GFAP) (p < 0.05), and leucine rich alpha-2-glycoprotein 1 (LRG1) (p < 0.01) in the DRG of old GLA KO mice compared to old WT. Dysregulation of immune-related genes may be linked to lower gene expression levels of the pain-associated ion channels calcium-activated potassium channel 3.1 (KCa3.1) and transient receptor potential ankyrin 1 channel (TRPA1). Ion channel expression might further be disturbed by impaired sphingolipid recruitment mediated via the lipid raft marker flotillin-1 (FLOT1). This impairment is represented by an increased number of FLOT1+ DRG neurons with a membranous expression pattern in old GLA KO mice compared to young GLA KO, young WT, and old WT mice (p < 0.001 each). Further, we provide evidence for aberrant behavior of GLA KO mice, which might be linked to dysregulated ion channel gene expression levels and disturbed FLOT1 distribution patterns. Behavioral testing revealed mechanical hypersensitivity in young (p < 0.01) and old (p < 0.001) GLA KO mice compared to WT, heat hypersensitivity in young GLA KO mice (p < 0.001) compared to WT, age-dependent heat hyposensitivity in old GLA KO mice (p < 0.001) compared to young GLA KO mice, and cold hyposensitivity in young (p < 0.001) and old (p < 0.001) GLA KO mice compared to WT, which well reflects the clinical phenotype observed in FD patients.

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Flotillin-1 Interacts With and Sustains the Surface Levels of TRPV2 Channel

Cited by 8 publications

References 60 publications

ELMOD3-Rab1A-Flotillin2 cascade regulates lumen formation via vesicle trafficking inCionanotochord

ELMOD3-Rab1A-Flotillin2 cascade regulates lumen formation via vesicle trafficking inCionanotochord

m6A Regulates the Stability of Cellular Transcripts Required for Efficient KSHV Lytic Replication

Dysregulation of Immune Response Mediators and Pain-Related Ion Channels Is Associated with Pain-like Behavior in the GLA KO Mouse Model of Fabry Disease

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