WIPI proteins: essential PtdIns3<i>P</i> effectors at the nascent autophagosome

Proikas‐Cezanne, Tassula; Takacs, Zsuzsanna; Dönnes, Pierre; Kohlbacher, Oliver

doi:10.1242/jcs.146258

Cited by 241 publications

(248 citation statements)

References 157 publications

(237 reference statements)

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“…While many effector proteins use PX or FYVE domains to bind to PI3P [51], the primary PI3P effectors during canonical autophagy are the WIPI proteins that utilize an alternative lipid binding domain, the WD β-propeller PROPIN [52]. In early autophagosome structures WIPI2 simultaneous binds to PI3P generated by VPS34 and to ATG16L1 [53].…”

Section: Pi3k and Rubicon Are Required For Lapmentioning

confidence: 99%

LC3-Associated Phagocytosis and Inflammation

Heckmann

Boada-Romero

Cunha

et al. 2017

Journal of Molecular Biology

223

202

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LC3-associated phagocytosis (LAP) is a novel form of non-canonical autophagy where LC3 (microtubule-associated protein 1A/1B-light chain 3) is conjugated to phagosome membranes using a portion of the canonical autophagy machinery. The impact of LAP to immune regulation is best characterized in professional phagocytes, in particular macrophages, where LAP has instrumental roles in the clearance of extracellular particles including apoptotic cells and pathogens. Binding of dead cells via receptors present on the macrophage surface results in the translocation of the autophagy machinery to the phagosome and ultimately LC3 conjugation. These events promote a rapid form of phagocytosis that produces an “immunologically silent” clearance of the apoptotic cells. Consequences of LAP deficiency include a decreased capacity to clear dying cells and the establishment of a lupus-like autoimmune disease in mice. The ability of LAP to attenuate autoimmunity likely occurs through the dampening of pro-inflammatory signals upon engulfment of dying cells and prevention of autoantigen presentation to other immune cells. However, it remains unclear how LAP shapes both the activation and outcome of the immune response at the molecular level. Herein, we provide a detailed review of LAP and its known roles in the immune response and provide further speculation on the putative mechanisms by which LAP may regulate immune function, perhaps through the metabolic reprogramming and polarization of macrophages.

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Section: Pi3k and Rubicon Are Required For Lapmentioning

confidence: 99%

LC3-Associated Phagocytosis and Inflammation

Heckmann

Boada-Romero

Cunha

et al. 2017

Journal of Molecular Biology

223

202

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“…The latter then serve as platforms to recruit the double FYVE domain-containing protein 1 (DFCP1) and the WD-repeat protein interacting with phosphoinositides (WIPI) proteins, which are homologous to the yeast Atg18 [59,60,61]. DFCP1 interaction with PtdIns3 P promotes its translocation to an ER-localized punctate compartment enriched in PtdIns3 P and autophagosomal proteins.…”

Section: Phosphatidylinositol 3-phosphate (Ptdins3p) An Endosomalmentioning

confidence: 99%

“…Moreover, WIPI 1 and 2 are essential for the recruitment of the downstream autophagy partners Atg12, Atg5 and Atg16L and, thus, for the subsequent steps of the autophagy process [62]. Indeed, mutations affecting the binding of human WIPI proteins to PtdIns3 P have been observed in cancers and neurodegenerative diseases, indicating an important biological role of PtdIns3 P in the regulation of autophagy and beyond [61]. …”

Section: Phosphatidylinositol 3-phosphate (Ptdins3p) An Endosomalmentioning

confidence: 99%

Phosphoinositides, Major Actors in Membrane Trafficking and Lipid Signaling Pathways

Craene

Bertazzi

Bär

et al. 2017

IJMS

171

149

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Abstract:Phosphoinositides are lipids involved in the vesicular transport of proteins and lipids between the different compartments of eukaryotic cells. They act by recruiting and/or activating effector proteins and thus are involved in regulating various cellular functions, such as vesicular budding, membrane fusion and cytoskeleton dynamics. Although detected in small concentrations in membranes, their role is essential to cell function, since imbalance in their concentrations is a hallmark of many cancers. Their synthesis involves phosphorylating/dephosphorylating positions D3, D4 and/or D5 of their inositol ring by specific lipid kinases and phosphatases. This process is tightly regulated and specific to the different intracellular membranes. Most enzymes involved in phosphoinositide synthesis are conserved between yeast and human, and their loss of function leads to severe diseases (cancer, myopathy, neuropathy and ciliopathy).Keywords: lipids; membrane trafficking; vesicles; phosphoinositides; phosphatase; kinase Phosphoinositides in Cellular Membranes Lipids, Major Membrane ComponentsThe dynamic modulation of the physicochemical properties of membranes is required for eukaryotic cells function. Indeed, cells live in an environment characterized by temperature, relative humidity, pH, sun exposure, osmotic pressure and nutrient variations. Living organisms have to adapt to variations of these different factors in order to keep their intracellular balance. Eukaryotic cells have achieved this by adopting a compartmentalized organization, which minimizes the intracellular variations resulting from extracellular fluctuations. The plasma membrane is the first barrier separating the cytoplasm from the extracellular medium. Its composition ensures a mechanical protection, but also allows exchanges with the medium through transporters and receptors, as a form of very selective permeability.Membranes are composed of two phospholipid leaflets organized as a bilayer in which sterols, glycolipids and proteins are inserted. The phospholipids of this bilayer are amphiphilic with a hydrophilic group (head) linked to a hydrophobic group (tail) ( Figure 1A). In the bilayer, the hydrophobic groups face each other, thus creating a hydrophobic space in between them, which ensures its role as a barrier. This property is very important for the anchoring of hydrophobic molecules, such as sterols or ceramides, transmembrane domains or the lipid anchor of proteins. The lipid composition of membranes varies according to the organism (eukaryotes or prokaryotes), the cell type (among the different tissues of a multicellular organism), the membrane type (plasma Int.

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“…This complex generates PtdIns3P (phosphatidylinositol 3-phosphate) and this compound is subsequently bound by effectors like WIPI (WDrepeat-interacting phosphoinositide proteins) and DFCP1 (double FYVE domain-containing protein 1) that are necessary for the biogenesis of the autophagosome (reviewed in [28,29]) Subsequently, two ubiquitin-like conjugation systems participate in the process: the first one, leads to the generation of the ATG5-ATG12 conjugate that then, associates to ATG16L. This latter protein complex acts as an E3-like enzyme in the second conjugation system, which contributes to the binding of phosphatidylethanolamine (PE) to the ubiquitin-like Atg8/LC3 (microtubule-associated protein 1-light chain 3), ( [30,31] and reviewed in [32]).…”

Section: Critical Core Machinery Involved In Autophagymentioning

confidence: 99%

Autophagy and proteins involved in vesicular trafficking

2015

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a b s t r a c tAutophagy is an intracellular degradation system that, as a basic mechanism it delivers cytoplasmic components to the lysosomes in order to maintain adequate energy levels and cellular homeostasis. This complex cellular process is activated by low cellular nutrient levels and other stress situations such as low ATP levels, the accumulation of damaged proteins or organelles, or pathogen invasion. Autophagy as a multistep process involves vesicular transport events leading to tethering and fusion of autophagic vesicles with several intracellular compartments. This review summarizes our current understanding of the autophagic pathway with emphasis in the trafficking machinery (i.e. Rabs GTPases and SNAP receptors (SNAREs)) involved in specific steps of the pathway.

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WIPI proteins: essential PtdIns3P effectors at the nascent autophagosome

Cited by 241 publications

References 157 publications

LC3-Associated Phagocytosis and Inflammation

LC3-Associated Phagocytosis and Inflammation

Phosphoinositides, Major Actors in Membrane Trafficking and Lipid Signaling Pathways

Autophagy and proteins involved in vesicular trafficking

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