Regulation of TRPML1 function

Waller-Evans, Helen; Lloyd-Evans, Emyr

doi:10.1042/bst20140311

Cited by 26 publications

(18 citation statements)

References 45 publications

(67 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Trehalosemediated nuclear translocation of TFEB and autophagy activation in macrophages was also recently implicated as a potential therapy for atherosclerosis [52]. Activation of the MCOLN1 channel is dependent on its interaction with PtdIns (3,5)P2, a product of the enzymatic action of PIKFYVE [39,53]. The role of PIKFYVE in regulating autophagy in itself is debatable, with literature references supporting both proand anti-autophagy properties.…”

Section: Discussionmentioning

confidence: 99%

“…The role of PIKFYVE in regulating autophagy in itself is debatable, with literature references supporting both proand anti-autophagy properties. Thus, while PIKFYVE through PtdIns(3,5)P2 can activate MCOLN1 [39,53], it is also reported that both PtdIns(3,5)P2, as well as PndIns5P, can activate MTOR pathway, which should negatively regulate autophagy [54,55]. In fact, PtdIns(3,5)P2 serves as the precursor for entire cellular PtdIns5P content, most likely through some phosphatase activity [38].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Trehalose limits opportunistic mycobacterial survival during HIV co-infection by reversing HIV-mediated autophagy block

et al. 2020

View full text Add to dashboard Cite

Opportunistic bacterial infections amongst HIV-infected individuals contribute significantly to HIVassociated mortality. The role of HIV-mediated modulation of innate mechanisms like autophagy in promoting opportunistic infections, however, remains obscure. Here we show, HIV reactivation in or infection of macrophages inhibits autophagy and helps the survival of pathogenic Mycobacterium tuberculosis (Mtb) and nonpathogenic non-tuberculous mycobacterial strains (NTMs). The HIVmediated impairment of xenophagy flux facilitated bacterial survival. Activation of autophagy by trehalose could induce xenophagy flux and kill intracellular Mtb or NTMs either during single or coinfections. Trehalose, we delineate, activates PIKFYVE leading to TFEB nuclear translocation in MCOLN1dependent manner to induce autophagy. Remarkably, trehalose significantly reduced HIV-p24 levels in ex-vivo-infected PBMCs or PBMCs from treatment-naive HIV patients and also controlled mycobacterial survival within Mtb-infected animals. To conclude, we report leveraging of HIV-mediated perturbed host innate-immunity by opportunistic bacterial pathogens and show an attractive therapeutic strategy for HIV and associated co-morbidities.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Trehalose limits opportunistic mycobacterial survival during HIV co-infection by reversing HIV-mediated autophagy block

et al. 2020

View full text Add to dashboard Cite

show abstract

“…274 ), and displayed an additive effect in combination with the endogenous activator phospha tidylinositol3,5bisphosphate (PtdIns(3,5)P2) 274,303 . An analogue of SF22, in which chlorine on the thiophene had been replaced by a methyl group, showed greater efficacy on TRPML1 activation 303,304 . Another molecule called ML SA1 (FigS 2,3), acting as a mucolipin synthetic agonist, also showed an additive effect with endogenous PtdIns(3,5)P2 on TRPML1 channels 305 .…”

Section: V-atpase Inhibitorsmentioning

confidence: 99%

Lysosomes as a therapeutic target

Bonam

Wang

Muller

2019

Nat Rev Drug Discov

495

374

View full text Add to dashboard Cite

| Lysosomes are membrane-bound organelles with roles in processes involved in degrading and recycling cellular waste, cellular signalling and energy metabolism. Defects in genes encoding lysosomal proteins cause lysosomal storage disorders, in which enzyme replacement therapy has proved successful. Growing evidence also implicates roles for lysosomal dysfunction in more common diseases including inflammatory and autoimmune disorders, neurodegenerative diseases, cancer and metabolic disorders. With a focus on lysosomal dysfunction in autoimmune disorders and neurodegenerative diseases -including lupus, rheumatoid arthritis, multiple sclerosis, Alzheimer disease and Parkinson disease -this Review critically analyses progress and opportunities for therapeutically targeting lysosomal proteins and processes, particularly with small molecules and peptide drugs.

show abstract

“…They are likely filled by Ca 2+ -H + exchange (Melchionda et al, 2016) and express members of the transient receptor potential mucolipin (TRPML) and two-pore channel (TPC) families to effect Ca 2+ release (Grimm et al, 2012; Kiselyov et al, 2012; Patel, 2015; Waller-Evans and Lloyd-Evans, 2015). Three TRPML isoforms are present in humans (García-Añoveros and Wiwatpanit, 2014).…”

Section: Introductionmentioning

confidence: 99%

Endo-lysosomal TRP mucolipin-1 channels trigger global ER Ca2+ release and Ca2+ influx

Kilpatrick

Yates

Grimm

et al. 2016

Journal of Cell Science

View full text Add to dashboard Cite

Transient receptor potential (TRP) mucolipins (TRPMLs), encoded by the MCOLN genes, are patho-physiologically relevant endo-lysosomal ion channels crucial for membrane trafficking. Several lines of evidence suggest that TRPMLs mediate localised Ca2+ release but their role in Ca2+ signalling is not clear. Here, we show that activation of endogenous and recombinant TRPMLs with synthetic agonists evoked global Ca2+ signals in human cells. These signals were blocked by a dominant-negative TRPML1 construct and a TRPML antagonist. We further show that, despite a predominant lysosomal localisation, TRPML1 supports both Ca2+ release and Ca2+ entry. Ca2+ release required lysosomal and ER Ca2+ stores suggesting that TRPMLs, like other endo-lysosomal Ca2+ channels, are capable of ‘chatter’ with ER Ca2+ channels. Our data identify new modalities for TRPML1 action.

show abstract

Regulation of TRPML1 function

Cited by 26 publications

References 45 publications

Trehalose limits opportunistic mycobacterial survival during HIV co-infection by reversing HIV-mediated autophagy block

Trehalose limits opportunistic mycobacterial survival during HIV co-infection by reversing HIV-mediated autophagy block

Lysosomes as a therapeutic target

Endo-lysosomal TRP mucolipin-1 channels trigger global ER Ca2+ release and Ca2+ influx

Contact Info

Product

Resources

About