The lipid kinase PI4KIIIβ preserves lysosomal identity

Sridhar, Sunandini; Patel, Bindi; Aphkhazava, David; Macian, Fernando; Santambrogio, Laura; Shields, Dennis; Cuervo, Ana María

doi:10.1038/emboj.2012.341

Cited by 112 publications

(146 citation statements)

References 37 publications

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“…PI4P generated by the vertebrate PI4KIIIβ, and its yeast homolog, Pik1, has previously been shown to directly regulate sorting from lysosomes to preserve lysosomal identity (13) and Atg9 Golgi trafficking (17), as well as indirectly by supporting PIP 2 synthesis to promote autophagosome biogenesis (18) and autophagic lysosome reformation (13,14). Here we show that the PI4P generated by PI4KIIα on autophagosomes has a different and unique role.…”

Section: Discussionmentioning

confidence: 82%

“…Because PIP5Kβ, which generates PIP 2 from PI4P, and PI4KIIIβ, the only PI4K that has been previously implicated in autophagy, promote autophagic lysosome reformation downstream of A:L fusion (13,14), we compared the effect of their depletion (documented in Fig. S6A) with that of PI4KIIα depletion.…”

Section: Pi4kiiα Depletion Generates Abnormally Large Autophagosomesmentioning

confidence: 99%

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GABARAPs regulate PI4P-dependent autophagosome:lysosome fusion

Wang

Sun

Zhu

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

179

164

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The Atg8 autophagy proteins are essential for autophagosome biogenesis and maturation. The γ-aminobutyric acid receptor-associated protein (GABARAP) Atg8 family is much less understood than the LC3 Atg8 family, and the relationship between the GABARAPs' previously identified roles as modulators of transmembrane protein trafficking and autophagy is not known. Here we report that GABARAPs recruit palmitoylated PI4KIIα, a lipid kinase that generates phosphatidylinositol 4-phosphate (PI4P) and binds GABARAPs, from the perinuclear Golgi region to autophagosomes to generate PI4P in situ. Depletion of either GABARAP or PI4KIIα, or overexpression of a dominant-negative kinase-dead PI4KIIα mutant, decreases autophagy flux by blocking autophagsome:lysosome fusion, resulting in the accumulation of abnormally large autophagosomes. The autophagosome defects are rescued by overexpressing PI4KIIα or by restoring intracellular PI4P through "PI4P shuttling." Importantly, PI4KIIα's role in autophagy is distinct from that of PI4KIIIβ and is independent of subsequent phosphatidylinositol 4,5 biphosphate (PIP 2 ) generation. Thus, GABARAPs recruit PI4KIIα to autophagosomes, and PI4P generation on autophagosomes is critically important for fusion with lysosomes. Our results establish that PI4KIIα and PI4P are essential effectors of the GABARAP interactome's fusion machinery.autophagy | GABARAP | PI4P | PI4KIIα | autophagosome:lysosome fusion

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Section: Discussionmentioning

confidence: 82%

Section: Pi4kiiα Depletion Generates Abnormally Large Autophagosomesmentioning

confidence: 99%

GABARAPs regulate PI4P-dependent autophagosome:lysosome fusion

Wang

Sun

Zhu

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

179

164

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“…This data suggests that similarly to the Vps34-MTM1-PI4K2α-complex on early endosomes, a Vps34-MTMR2-PI4K2α-complex might regulate transport and recycling from late endosomes. Thus, a systematic and comprehensive analysis of the myotubularin-PI kinase interactome should include all endosomal PI kinases such as type II PI4Ks, late endosomal PIKfyve or lysosomal PI4K3β (Sridhar, Patel et al 2013) besides PI3Ks.…”

Section: Membrane Recruitment Of Mtm1 Is Regulated By Lipid and Protementioning

confidence: 99%

“…Thus, late endosomal recycling might involve a different subset of 4'-and 3'-metabolising enzymes, i.e. the lysosomal PI4K3β (Sridhar, Patel et al 2013) and MTMR2.…”

Section: Late Endosomal Recycling Contributes To β1-integrin Trafficmentioning

confidence: 99%

A phosphoinositide conversion mechanism for exit from endosomes

Ketel¹,

Krauß²,

Nicot³

et al. 2016

Nature

165

177

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I owe special thanks to Marnix Wieffer and Michael Krauß, who spent a lot of time helping me to get started in the lab, to overcome numerous experimental problem, I was not sure how to deal with, and frequently joined in discussions about my project with excellent advice. I am really grateful for your experimental support, Michael, and the time you invested in the project during our paper revision.Further, I would like to thank Jocelyn Laporte and his group, especially Anne-Sophie Nicot, at the IGBMC in Strasbourg for their support and a very fruitful collaboration, and Carsten Schultz and his group at the EMBL in Heidelberg for their support and constant supply with PIP/AMs. I owe special thanks to Dmytro Puchkov for the ultrastructural analysis and Eberhard Krause for mass spectrometry done within this project. I also need to acknowledge Markus Wenk and Federico Torta at the Singapore Lipidomics Incubator for joining the project at a very late stage, when we urgently needed help from lipidomics specialists. It was a pity that experiments did not work out as planned.I would further like to express my gratitude to two very skilled technicians in the AG Haucke lab: Silke Zillmann and Delia Löwe. Without your help it would have been impossible to achieve so much within the limited amount of time I had during the paper revision. by VPS34-IN1 treatment................................................... 52 2.3.11 Fluorescence microscopy................................................................................. 53 2.3.12 Flow cytometry............................................................................................ III SummaryPhosphoinositides (PIs) are a minor class of short-lived phospholipids that serve as crucial signposts of membrane identity. Thereby, PIs full fill important functions in cell signaling and membrane transport. PI 4-phosphates such as phosphatitylinositol-4-phosphate (PI(4)P) and phosphatitylinositol-4,5-bisphosphate (PI(4,5)P 2 ) are enriched at the plasma membrane (PM), on secretory organelles and lysosomes, while PI 3-phosphates, i.e.phosphatitylinositol-3-phosphate (PI(3)P), are a hallmark of the endosomal system.Directional transport between these compartments, thus, requires regulated PI conversion.However, PI conversion in exit from PI(3)P-enriched endosomes en route to the PI(4)P-and PI(4,5)P 2 -positive PM in endosomal recycling remained unknown.Here, we report that cargo exit from endosomes requires removal of PI(3)P by the PI(3)P 3-phosphatase myotubularin 1 (MTM1), and concomitant PI(4)P synthesis by PI 4-kinase type II α (PI4K2α). Loss of MTM1 causes endosomal accumulation of PI(3)P and PI(3)P effector proteins, i.e. sorting nexins, Kif16b-mediated outward traffic of PI(3)P containing endosomes and sub-plasmalemmal accumulation of exocytosis-deficient endosomes. As PI4K2α associates with MTM1 and thereby facilitates membrane recruitment of MTM1, these phenotypic changes are mimicked by loss of PI4K2α. The conversion of PI(3)P-to-PI(4)P is paralleled by a switch i...

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“…To further investigate extra-lysosomal EGFP-RAB26Q123L vesicle localization, we costained with EEA1, giantin and the CI-M6PR (data not shown) revealing no substantial colocalization with Golgi, but partial overlap with the endosomal compartments. Thus, we conclude RAB26 requires prenylation and GTP binding to target to lysosomes, and dynamic GTP cycling to maintain localization on lysosomes and avoid trafficking to other membranes as lysosomes recycle (Sridhar et al, 2013). …”

Section: Rab26 Localizes Specifically To Lamp1 Lysosomal Membraneassomentioning

confidence: 99%

RAB26 coordinates lysosome traffic and mitochondrial localization

Jin

Mills

2014

Journal of Cell Science

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As they mature, professional secretory cells like pancreatic acinar and gastric chief cells induce the transcription factor MIST1 (also known as BHLHA15) to substantially scale up production of large secretory granules in a process that involves expansion of apical cytoplasm and redistribution of lysosomes and mitochondria. How a scaling factor like MIST1 rearranges cellular architecture simply by regulating expression levels of its transcriptional targets is unknown. RAB26 is a MIST1 target whose role in MIST1-mediated secretory cell maturation is also unknown. Here, we confirm that RAB26 expression, unlike most Rabs which are ubiquitously expressed, is tissue specific and largely confined to MIST1-expressing secretory tissues. Surprisingly, functional studies showed that RAB26 predominantly associated with LAMP1/cathepsin D lysosomes and not directly with secretory granules. Moreover, increasing RAB26 expression -by inducing differentiation of zymogensecreting cells or by direct transfection -caused lysosomes to coalesce in a central, perinuclear region. Lysosome clustering in turn caused redistribution of mitochondria into distinct subcellular neighborhoods. The data elucidate a novel function for RAB26 and suggest a mechanism for how cells could increase transcription of key effectors to reorganize subcellular compartments during differentiation.

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The lipid kinase PI4KIIIβ preserves lysosomal identity

Cited by 112 publications

References 37 publications

GABARAPs regulate PI4P-dependent autophagosome:lysosome fusion

GABARAPs regulate PI4P-dependent autophagosome:lysosome fusion

A phosphoinositide conversion mechanism for exit from endosomes

RAB26 coordinates lysosome traffic and mitochondrial localization

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