Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo

Dowdle, William E.; Nyfeler, Beat; Nagel, Jane; Elling, R.A.; Liu, Shanming; Triantafellow, Ellen; Menon, Suchithra; Wang, Zuncai; Honda, Ayako; Pardee, Gwynn; Cantwell, John; Luu, Catherine A.; Cornella-Taracido, Ivan; Harrington, Edmund; Fekkes, Peter; Lei, Hong; Fang, Qing; Digan, Mary Ellen; Burdick, Debra; Powers, Andrew F.; Helliwell, Stephen B.; d’Aquin, Simon; Bastien, Julie; Wang, Henry; Wiederschain, Dmitri; Kuerth, Jenny; Bergman, Philip J.; Schwalb, David J.; Thomas, Jason R.; Ugwonali, Savuth; Harbinski, Fred; Tallarico, John A.; Wilson, Christopher J.; Myer, Vic E.; Porter, Jeffery A.; Bussiere, Dirksen E.; Finan, Peter M.; Labow, Mark; Mao, Xiaohong; Hamann, Lawrence G.; Manning, Brendan D.; Valdez, Reginald; Nicholson, Thomas; Schirle, Markus; Knapp, Mark; Keaney, Erin P.; Murphy, Leon O.

doi:10.1038/ncb3053

Cited by 546 publications

(498 citation statements)

References 71 publications

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“…187 This molecular dissection of PIK3C3 paved the way for the subsequent development of novel inhibitors that fit well within the PIK3C3 ATP cavity. A number of recent studies reported new PIK3C3 inhibitors, including VPS34-IN1, 184 Compound 31 (a tetrahydropyrimidopyrimidinone derivative), 186 PIK-III, 185 and SAR405; 183 among them, Compound 31 and SAR405 exhibit the highest potency (IC 50 PIK3C3 equals 2 nM and 1.2 nM, respectively) and favorable selectivity toward PIK3C3. 183,186 Notably, PIK-III and SAR405, both of which bind the ATP binding pocket of PIK3C3, exert efficient inhibition on autophagy as well as LC3 lipidation.…”

Section: Ptdins3k and Pi3k Inhibitors And Their Application In Autophmentioning

confidence: 99%

“…26,175 Inspiring progress has been made recently in the development of effective and specific inhibitors targeting PIK3C3. [183][184][185][186] An early study resolved the molecular structure of PIK3C3, and revealed that PIK3C3 has a smaller and more rigid ATP binding pocket than that of PIK3CG, which restricts the binding of classical PI3K inhibitors. 187 This molecular dissection of PIK3C3 paved the way for the subsequent development of novel inhibitors that fit well within the PIK3C3 ATP cavity.…”

Section: Ptdins3k and Pi3k Inhibitors And Their Application In Autophmentioning

confidence: 99%

“…183,186 Notably, PIK-III and SAR405, both of which bind the ATP binding pocket of PIK3C3, exert efficient inhibition on autophagy as well as LC3 lipidation. 183,185 The application of PIK-III led to the identification of a novel substrate of selective autophagy, NCOA4, which mediates the degradation of ferritin and turnover of iron. 185 Moreover, SAR405 displays a potential anticancer therapeutic property, as it shows synergistic antiproliferative activity in combination with the MTOR inhibitor everolimus.…”

Section: Ptdins3k and Pi3k Inhibitors And Their Application In Autophmentioning

confidence: 99%

“…183,185 The application of PIK-III led to the identification of a novel substrate of selective autophagy, NCOA4, which mediates the degradation of ferritin and turnover of iron. 185 Moreover, SAR405 displays a potential anticancer therapeutic property, as it shows synergistic antiproliferative activity in combination with the MTOR inhibitor everolimus. 183 These PIK3C3 inhibitors will prove to be valuable tools in delineating the function of class III PtdIns3K in each stage of autophagy as well as other cellular processes; also, they are promising pharmaceutical candidates for augmenting the activity of current anticancer drugs as well as having a potential application to other diseases.…”

Section: Ptdins3k and Pi3k Inhibitors And Their Application In Autophmentioning

confidence: 99%

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Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

2015

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Abbreviations: 3-MA, 3-methyladenine; AMBRA1, autophagy/Beclin 1 regulator 1; ATG, autophagy related; ATM, ATM serine/threonine kinase; ATR, ATR serine/threonine kinase; BH3, Bcl-2 homology 3; CCD, coiled-coil domain; CDK, cyclin-dependent kinase; CISD2, CDGSH iron sulfur domain 2; class I/II PI3K, class I/II phosphoinositide 3-kinase; class III PtdIns3K, class III phosphatidylinositol 3-kinase; DAPK1, death-associated protein kinase 1; DDR, DNA damage response; EIF4EBP1, eukaryotic translation initiation factor 4E binding protein 1; ER, endoplasmic reticulum; FOXO, forkhead box O; FYCO1, FYVE and coiledcoil domain containing 1; GAP, GTPase-activating protein; HMGB1, high mobility group box 1; HSPA1A, heat shock 70kDa protein 1A; IR, ionizing radiation; MAPK8, mitogen-activated protein kinase 8; MEFs, mouse embryonic fibroblasts; MTMR, myotubularin-related protein; MTOR, mechanistic target of rapamycin (serine/threonine kinase); MTORC1, mechanistic target of rapamycin complex 1; MVBs, spherical multivesicular bodies; NRBF2, nuclear receptor binding factor 2; PAS, phagophore assembly site; PDPK1, 3-phosphoinositide dependent protein kinase 1; PE, phosphatidylethanolamine; PIKFYVE, phosphoinositide kinase, FYVE finger containing; PINK1, PTEN-induced putative kinase 1; PtdIns3K-C1, class III phosphatidylinositol 3-kinase complex I; PtdIns3K-C2, class III phosphatidylinositol 3-kinase complex II; PKB, protein kinase B; PRKA, protein kinase, AMP-activated; PRKD1, protein kinase D1; PRKDC, protein kinase, DNA-activated, catalytic polypeptide; PtdIns5P, phosphatidylinositol 5-phosphate; PtdIns4P, phosphatidylinositol 4-phosphate; PtdIns(4,5)P 2 , phosphatidylinositol 4,5-bisphosphate; PtdIns3P, phosphatidylinositol 3-phosphate; PtdIns(3,5)P 2 , phosphatidylinositol 3,5-bisphosphate; PtdIns(3,4,5)P 3 , phosphatidylinositol 3,4,5-trisphosphate; RHEB, Ras homolog enriched in brain; RPS6KB1, ribosomal protein S6 kinase, 70kDa, polypeptide 1; SQSTM1, sequestosome 1; TECPR1, tectonin b-propeller repeat containing 1; TFEB, transcription factor EB; TRIM28, tripartite motif containing 28; TSC, tuberous sclerosis; UV, ultraviolet; UVRAG, UV radiation resistance associated; WDFY3, WD repeat and FYVE domain containing 3; WIPI, WD repeat domain, phosphoinositide interacting; ZFYVE1, zinc finger, FYVE domain containing 1.Autophagy is an evolutionarily conserved and exquisitely regulated self-eating cellular process with important biological functions. Phosphatidylinositol 3-kinases (PtdIns3Ks) and phosphoinositide 3-kinases (PI3Ks) are involved in the autophagic process. Here we aim to recapitulate how 3 classes of these lipid kinases differentially regulate autophagy. Generally, activation of the class I PI3K suppresses autophagy, via the well-established PI3K-AKT-MTOR (mechanistic target of rapamycin) complex 1 (MTORC1) pathway. In contrast, the class III PtdIns3K catalytic subunit PIK3C3/Vps34 forms a protein complex with BECN1 and PIK3R4 and produces phosphatidylinositol 3-phosphate (PtdIns3P), which is required for the initiati...

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Section: Ptdins3k and Pi3k Inhibitors And Their Application In Autophmentioning

confidence: 99%

Section: Ptdins3k and Pi3k Inhibitors And Their Application In Autophmentioning

confidence: 99%

Section: Ptdins3k and Pi3k Inhibitors And Their Application In Autophmentioning

confidence: 99%

Section: Ptdins3k and Pi3k Inhibitors And Their Application In Autophmentioning

confidence: 99%

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Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

2015

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“…Upon cystine deprivation, autophagy is activated to degrade the iron storage protein ferritin, which is mediated by the cargo receptor NCOA4. Such NCOA4-mediated autophagic degradation of ferritin (ferroptinophagy) [24][25][26][27], by maintaining cellular labile iron contents, promotes the accumulation of cellular ROS and consequent ferroptotic cell death.…”

Section: Introductionmentioning

confidence: 99%

Ferroptosis is an autophagic cell death process

et al. 2016

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Ferroptosis is an iron-dependent form of regulated necrosis. It is implicated in various human diseases, including ischemic organ damage and cancer. Here, we report the crucial role of autophagy, particularly autophagic degradation of cellular iron storage proteins (a process known as ferritinophagy), in ferroptosis. Using RNAi screening coupled with subsequent genetic analysis, we identified multiple autophagy-related genes as positive regulators of ferroptosis. Ferroptosis induction led to autophagy activation and consequent degradation of ferritin and ferritinophagy cargo receptor NCOA4. Consistently, inhibition of ferritinophagy by blockage of autophagy or knockdown of NCOA4 abrogated the accumulation of ferroptosis-associated cellular labile iron and reactive oxygen species, as well as eventual ferroptotic cell death. Therefore, ferroptosis is an autophagic cell death process, and NCOA4-mediated ferritinophagy supports ferroptosis by controlling cellular iron homeostasis.

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Mitochondrial ferritin expression in human macrophages is facilitated by thrombin‐mediated cleavage under hypoxia

2022

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Ferritins are iron storage proteins, which maintain cellular iron homeostasis. Among these proteins, the ferritin heavy chain is well characterized, but the regulatory principles of mitochondrial ferritin (FTMT) remain elusive. FTMT appears to be cleaved from a 27 kDa to a 22 kDa form. In human macrophages, FTMT increased under hypoxia in a hypoxia-inducible factor 2-dependent manner. Occurrence of FTMT resulted from cleavage by thrombin, which was supplied by serum. Inhibition of thrombin as well as serum removal decreased FTMT, while supplementation of thrombin under serum-deprived conditions restored its expression. Besides hypoxia, thrombin facilitated FTMT expression after treatment with the ferroptosis inducer RSL3 and the pro-inflammatory stimulus lipopolysaccharide. This study provides insights into the regulation of FTMT under hypoxia and identifies thrombin as a FTMT maturation-associated peptidase.

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Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo

Cited by 546 publications

References 71 publications

Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

Ferroptosis is an autophagic cell death process

Mitochondrial ferritin expression in human macrophages is facilitated by thrombin‐mediated cleavage under hypoxia

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