Phosphatidylinositol 3,5-bisphosphate and Fab1p/PIKfyve underPPIn endo-lysosome function

Dove, Stephen K.; Dong, Kangzhen; Kobayashi, Takafumi; Williams, Fay Kathleen; Michell, Robert H.

doi:10.1042/bj20081950

Cited by 181 publications

(215 citation statements)

References 123 publications

(249 reference statements)

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“…PtdIns(3)P localizes to early endosomes and multivesicular bodies (Gillooly et al, 2000;Gillooly et al, 2003). PtdIns(3,5)P 2 is implicated in late endosomal/lysosomal function, although early endosomal effects have also been described (Dove et al, 2009). The evidence for the subcellular distribution of MTMs to early or late endosomal compartments is conflicting, in part due to a general problem in generating specific immunoreactive MTM antibodies (Robinson and Dixon, 2006), so that most reports have relied on recombinant MTM overexpression to evaluate enzyme subcellular localization.…”

Section: Introductionmentioning

confidence: 95%

The myotubularin phosphatase MTMR4 regulates sorting from early endosomes

Naughtin

Sheffield

Rahman

et al. 2010

Journal of Cell Science

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SummaryPhosphatidylinositol 3-phosphate [PtdIns(3)P] regulates endocytic trafficking and the sorting of receptors through early endosomes, including the rapid recycling of transferrin (Tfn). However, the phosphoinositide phosphatase that selectively opposes this function is unknown. The myotubularins are a family of eight catalytically active and six inactive enzymes that hydrolyse PtdIns(3)P to form PtdIns. However, the role each myotubularin family member plays in regulating endosomal PtdIns(3)P and thereby endocytic trafficking is not well established. Here, we identify the myotubularin family member MTMR4, which localizes to early endosomes and also to Rab11-and Sec15-positive recycling endosomes. In cells with MTMR4 knockdown, or following expression of the catalytically inactive MTMR4, MTMR4C407A , the number of PtdIns(3)P-decorated endosomes significantly increased. MTMR4 overexpression delayed the exit of Tfn from early endosomes and its recycling to the plasma membrane. By contrast, expression of MTMR4 C407A , which acts as a dominant-negative construct, significantly accelerated Tfn recycling. However, in MTMR4 knockdown cells Tfn recycling was unchanged, suggesting that other MTMs might also contribute to recycling. MTMR4 regulated the subcellular distribution of Rab11 and, in cells with RNAi-mediated knockdown of MTMR4, Rab11 was directed away from the pericentriolar recycling compartment. The subcellular distribution of VAMP3, a v-SNARE protein that resides in recycling endosomes and endosomederived transport vesicles, was also regulated by MTMR4. Therefore, MTMR4 localizes at the interface of early and recycling endosomes to regulate trafficking through this pathway.

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Section: Introductionmentioning

confidence: 95%

The myotubularin phosphatase MTMR4 regulates sorting from early endosomes

Naughtin

Sheffield

Rahman

et al. 2010

Journal of Cell Science

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“…Significantly less clear are the mechanistic details of how the PtdIns3P to PtdIns(3,5)P 2 conversion controls the lysosomal sorting process and the relevant downstream targets of the lipid PtdIns(3,5)P 2 (377). It is well established that Fab1p deleted yeast strains have huge vacuoles and impaired transport of CPY to the vacuole (498).…”

Section: Ptdins3p and Ptdins(35)p 2 In Endomembranesmentioning

confidence: 99%

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

Balla

2013

Physiological Reviews

1,393

1,655

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Phosphoinositides (PIs) make up only a small fraction of cellular phospholipids, yet they control almost all aspects of a cell's life and death. These lipids gained tremendous research interest as plasma membrane signaling molecules when discovered in the 1970s and 1980s. Research in the last 15 years has added a wide range of biological processes regulated by PIs, turning these lipids into one of the most universal signaling entities in eukaryotic cells. PIs control organelle biology by regulating vesicular trafficking, but they also modulate lipid distribution and metabolism via their close relationship with lipid transfer proteins. PIs regulate ion channels, pumps, and transporters and control both endocytic and exocytic processes. The nuclear phosphoinositides have grown from being an epiphenomenon to a research area of its own. As expected from such pleiotropic regulators, derangements of phosphoinositide metabolism are responsible for a number of human diseases ranging from rare genetic disorders to the most common ones such as cancer, obesity, and diabetes. Moreover, it is increasingly evident that a number of infectious agents hijack the PI regulatory systems of host cells for their intracellular movements, replication, and assembly. As a result, PI converting enzymes began to be noticed by pharmaceutical companies as potential therapeutic targets. This review is an attempt to give an overview of this enormous research field focusing on major developments in diverse areas of basic science linked to cellular physiology and disease.

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“…It has been shown that all type I IFN-inducing TLRs signal from the endolysosome (22). We hypothesized that intracellular TLR/ligand interaction may be compromised by PIKfyve inactivation because PIKfyve and its product PI(3,5P) 2 are regulators of endolysosome membrane traffic (23); that is, inhibition of PIKfyve could affect endosomal pH or cause a defect in ligand or receptor translocation in endolysosomes.…”

Section: Inactivation Of Pikfyve By Apilimod Selectively Inhibits Tlrmentioning

confidence: 99%

PIKfyve, a Class III Lipid Kinase, Is Required for TLR-Induced Type I IFN Production via Modulation of ATF3

Cai¹,

Xu²,

Kim³

et al. 2014

The Journal of Immunology

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Type I IFN plays a key role in antiviral responses. It also has been shown that deregulation of type I IFN expression following abnormal activation of TLRs contributes to the pathogenesis of systemic lupus erythematosus. In this study, we find that PIKfyve, a class III lipid kinase, is required for endolysosomal TLR-induced expression of type I IFN in mouse and human cells. PIKfyve binds to phosphatidylinositol 3-phosphate and synthesizes phosphatidylinositol 3,5-bisphosphate, and plays a critical role in endolysosomal trafficking. However, PIKfyve modulates type I IFN production via mechanisms independent of receptor and ligand trafficking in endolysosomes. Instead, pharmacological or genetic inactivation of PIKfyve rapidly induces expression of the transcription repressor ATF3, which is necessary and sufficient for suppression of type I IFN expression by binding to its promoter and blocking its transcription. Thus, we have uncovered a novel phosphoinositide-mediated regulatory mechanism that controls TLR-mediated induction of type I IFN, which may provide a new therapeutic indication for the PIKfyve inhibitor.

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Phosphatidylinositol 3,5-bisphosphate and Fab1p/PIKfyve underPPIn endo-lysosome function

Cited by 181 publications

References 123 publications

The myotubularin phosphatase MTMR4 regulates sorting from early endosomes

The myotubularin phosphatase MTMR4 regulates sorting from early endosomes

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

PIKfyve, a Class III Lipid Kinase, Is Required for TLR-Induced Type I IFN Production via Modulation of ATF3

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