OCRL1 engages with the F-BAR protein pacsin 2 to promote biogenesis of membrane-trafficking intermediates

Billcliff, Peter G.; Noakes, Christopher; Mehta, Zenobia B.; Yan, Guanhua; Mak, LokHang; Woscholski, Rüdiger; Lowe, Martin

doi:10.1091/mbc.e15-06-0329

Cited by 29 publications

(40 citation statements)

References 74 publications

(128 reference statements)

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“…5E). These data suggest that additional PtdIns (4,5)P 2 effectors and lipid metabolizing enzymes such as PI4K, PtdIns(4,5)P 2 phosphatases, SNX18, and others (18,19,31) might also be involved in fine tuning autophagy initiation.…”

Section: Discussionmentioning

confidence: 89%

PtdIns(4,5)P ₂ signaling regulates ATG14 and autophagy

Tan

Thapa

Liao

et al. 2016

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

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Autophagy is a regulated self-digestion pathway with fundamental roles in cell homeostasis and diseases. Autophagy is regulated by coordinated actions of a series of autophagy-related (ATG) proteins. The Barkor/ATG14(L)-VPS34 (a class III phosphatidylinositol 3-kinase) complex and its product phosphatidylinositol 3-phosphate [PtdIns(3)P] play key roles in autophagy initiation. ATG14 contains a C-terminal Barkor/ATG14(L) autophagosome-targeting sequence (BATS) domain that senses the curvature of PtdIns(3)P-containing membrane. The BATS domain also strongly binds PtdIns(4,5)P 2 , but the functional significance has been unclear. Here we show that ATG14 specifically interacts with type Iγ PIP kinase isoform 5 (PIPKIγi5), an enzyme that generates PtdIns(4,5)P 2 in mammalian cells. Autophagosomes have associated PIPKIγi5 and PtdIns(4,5)P 2 that are colocalized with late endosomes and the endoplasmic reticulum. PtdIns(4,5)P 2 generation at these sites requires PIPKIγi5. Loss of PIPKIγi5 results in a loss of ATG14, UV irradiation resistance-associated gene, and Beclin 1 and a block of autophagy. PtdIns(4,5)P 2 binding to the ATG14-BATS domain regulates ATG14 interaction with VPS34 and Beclin 1, and thus plays a key role in ATG14 complex assembly and autophagy initiation. This study identifies an unexpected role for PtdIns(4,5)P 2 signaling in the regulation of ATG14 complex and autophagy.M acroautophagy (referred to as autophagy from here on) is an intracellular self-digestion process conserved in all eukaryotes that maintains cell homeostasis and protects cells from various stresses. Autophagy involves the formation of doublemembrane autophagosomes that contain target cytoplasmic contents for lysosomal degradation (1). Autophagosome formation is driven by coordinated functions of a number of autophagy-related (ATG) proteins (2). The ATG14 (also called Barkor or ATG14L)-Beclin 1 (atg6 in yeast)-VPS34 (an enzyme involved in the cellular process of autophagy; class III PI3K) complex plays essential roles in the initiation steps of autophagy by generating phosphatidylinositol 3-phosphate [PtdIns(3)P] and recruiting PtdIns(3)P effectors (3-6). ATG14 functions by recruiting VPS34 to punctate structures associated with the endoplasmic reticulum (ER) (7), and then PtdIns(3)P, the product of VPS34, in turn binds the Barkor/Atg14 autophagosome targeting sequence (BATS) domain of ATG14 and regulates its membrane curvature sensing (8). The ATG14-BATS domain also binds PtdIns(4,5)P 2 without unknown functional relevance (8).Phosphoinositides are important lipid messengers in various membrane trafficking events. PtdIns(4,5)P 2 plays multiple roles at the plasma membrane, such as in endocytosis, exocytosis, focal adhesion assembly, and so on (9). However, recently studies have argued for roles for PtdIns(4,5)P 2 at intracellular compartments (10). The majority of PtdIns(4,5)P 2 in mammalian cells are generated by the type I phosphatidylinositol 4-phosphate (PIP) 5-kinase (PIPKI), of which there are three genes (α, β, and γ) each wit...

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Section: Discussionmentioning

confidence: 89%

PtdIns(4,5)P ₂ signaling regulates ATG14 and autophagy

Tan

Thapa

Liao

et al. 2016

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

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“…Our study gives weight to the possibility of functionally relevant amounts of PI(4,5)P 2 being present in the endocytic system under normal conditions. Recent research suggests that PI(4,5)P 2 and/or OCRL catalytic activity has a critical role in membrane traffic separate from its role in at the plasma membrane, including transition from early to late endosomes 65-68 and the transition from endosome to trans-Golgi 8,22 . The presence of conserved, endomembrane-specific interactors for OCRL argues against a function of OCRL solely as a cellular ‘housekeeper’, and suggests instead that OCRL-directed PI(4,5)P 2 on endosomes is assisted and directed by interaction with F&H proteins.…”

Section: Discussionmentioning

confidence: 99%

“…In different systems, fluid-phase endocytosis 20 and efficient ciliary traffic 21 require the interaction of OCRL with F&H proteins, suggesting their relevance to LS phenotypes. Ses2/IPIP27B recruits OCRL to sort cation-independent mannose-6-phosphate receptor (Ci-M6PR) 22 , a retromer cargo, demonstrating a requirement for OCRL-driven PI(4,5)P 2 dephosphorylation via F&H proteins in late endocytic traffic. The F&H binding patch is conserved in most species that express an OCRL-like protein, including a variety of protists and other unicellular eukaryotes including D. discoideum, Trypanosoma brucei 4 , Albugo candida (CCI48278.1, an Oomycete), and Cyanidioschyzon merolae (XP_005535444.1, a red alga), suggesting that interactions with F&H peptides are critical to OCRL function.…”

Section: Introductionmentioning

confidence: 99%

Lowe Syndrome-linked endocytic adaptors direct membrane cycling kinetics with OCRL inDictyostelium discoideum

Lüscher

FroÌˆhlich

Barisch

et al. 2019

Preprint

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SummaryMutations of the inositol 5-phosphatase OCRL cause Lowe Syndrome (LS), characterized by congenital cataract, low IQ and defective kidney proximal tubule resorption. A key subset of LS mutants abolishes OCRL’s interactions with endocytic adaptors containing F&H peptide motifs. Converging unbiased methods examining human peptides and the unicellular phagocytic organism Dictyostelium discoideum, reveal that, like OCRL, the Dictyostelium OCRL orthologue Dd5P4 binds two proteins closely related to the F&H proteins APPL1 and Ses1/2 (also referred to as IPIP27A/B). In addition, a novel conserved F&H interactor was identified, GxcU (in Dictyostelium) and the Cdc42-GEF Frabin (in human cells). Examining these proteins in Dictyostelium discoideum, we find that, like OCRL, Dd5P4 acts at well-conserved and physically distinct endocytic stations. Dd5P4 functions in coordination with F&H proteins to control membrane deformation at multiple stages of endocytosis, and suppresses GxcU-mediated activity during fluid-phase micropinocytosis. We also reveal that OCRL/Dd5P4 acts at the contractile vacuole, an exocytic osmoregulatory organelle. We propose F&H peptide-containing proteins may be key modifiers of LS phenotypes.

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“…3). Previous studies show that PACSIN2 localizes to early/sorting endosomes (EE/SE), tubular recycling endosomes, and the Golgi complex (28, 29). The novel interaction of PACSIN2 with rabenosyn‐5 further supports a role for PACSIN2 in the recycling of nephrin.…”

Section: Discussionmentioning

confidence: 99%

PACSIN2 accelerates nephrin trafficking and is up‐regulated in diabetic kidney disease

et al. 2017

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Nephrin is a core component of podocyte (glomerular epithelial cell) slit diaphragm and is required for kidney ultrafiltration. Down-regulation or mislocalization of nephrin has been observed in diabetic kidney disease (DKD), characterized by albuminuria. Here, we investigate the role of protein kinase C and casein kinase 2 substrate in neurons 2 (PACSIN2), a regulator of endocytosis and recycling, in the trafficking of nephrin and development of DKD. We observe that PACSIN2 is up-regulated and nephrin mislocalized in podocytes of obese Zucker diabetic fatty (ZDF) rats that have altered renal function. In cultured podocytes, PACSIN2 and nephrin colocalize and interact. We show that nephrin is endocytosed in PACSIN2-positive membrane regions and that PACSIN2 overexpression increases both nephrin endocytosis and recycling. We identify rabenosyn-5, which is involved in early endosome maturation and endosomal sorting, as a novel interaction partner of PACSIN2. Interestingly, rabenosyn-5 expression is increased in podocytes in obese ZDF rats, and, in vitro, its overexpression enhances the association of PACSIN2 and nephrin. We also show that palmitate, which is elevated in diabetes, enhances this association. Collectively, PACSIN2 is up-regulated and nephrin is abnormally localized in podocytes of diabetic ZDF rats. In vitro, PACSIN2 enhances nephrin turnover apparently via a mechanism involving rabenosyn-5. The data suggest that elevated PACSIN2 expression accelerates nephrin trafficking and associates with albuminuria

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OCRL1 engages with the F-BAR protein pacsin 2 to promote biogenesis of membrane-trafficking intermediates

Abstract: The Lowe syndrome protein OCRL1 binds via IPIP27A to the F-BAR protein pacsin 2 to promote the biogenesis of trafficking intermediates containing the mannose 6-phosphate receptor at the trans-Golgi network and endosomes.

Cited by 29 publications

References 74 publications

PtdIns(4,5)P ₂ signaling regulates ATG14 and autophagy

PtdIns(4,5)P ₂ signaling regulates ATG14 and autophagy

Lowe Syndrome-linked endocytic adaptors direct membrane cycling kinetics with OCRL inDictyostelium discoideum

PACSIN2 accelerates nephrin trafficking and is up‐regulated in diabetic kidney disease

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OCRL1 engages with the F-BAR protein pacsin 2 to promote biogenesis of membrane-trafficking intermediates

Abstract: The Lowe syndrome protein OCRL1 binds via IPIP27A to the F-BAR protein pacsin 2 to promote the biogenesis of trafficking intermediates containing the mannose 6-phosphate receptor at the trans-Golgi network and endosomes.

Cited by 29 publications

References 74 publications

PtdIns(4,5)P 2 signaling regulates ATG14 and autophagy

PtdIns(4,5)P 2 signaling regulates ATG14 and autophagy

Lowe Syndrome-linked endocytic adaptors direct membrane cycling kinetics with OCRL inDictyostelium discoideum

PACSIN2 accelerates nephrin trafficking and is up‐regulated in diabetic kidney disease

Contact Info

Product

Resources

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PtdIns(4,5)P ₂ signaling regulates ATG14 and autophagy

PtdIns(4,5)P ₂ signaling regulates ATG14 and autophagy