Read by QxMD icon Read


Shuhei Nakamura, Junya Hasegawa, Tamotsu Yoshimori
Macroautophagy (autophagy) is a multistep intracellular degradation system. Autophagosomes form, mature, and ultimately fuse with lysosomes, where their sequestered cargo molecules are digested. In contrast to autophagosome formation, our knowledge of autophagosome-lysosome fusion is limited. In a recent study, we identified a novel regulator of autophagy, INPP5E (inositol polyphosphate-5-phosphatase E), which is essential for autophagosome-lysosome fusion. INPP5E primarily functions in neuronal cells, and knockdown of the corresponding gene causes accumulation of autophagosomes by impairing fusion with lysosomes...
October 7, 2016: Autophagy
Kollu N Rao, Wei Zhang, Linjing Li, Manisha Anand, Hemant Khanna
Ciliary trafficking defects underlie the pathogenesis of severe human ciliopathies, including Joubert Syndrome (JBTS), Bardet-Biedl Syndrome, and some forms of retinitis pigmentosa (RP). Mutations in the ciliary protein RPGR (retinitis pigmentosa GTPase regulator) are common causes of RP-associated photoreceptor degeneration worldwide. While previous work has suggested that the localization of RPGR to cilia is critical to its functions, the mechanism by which RPGR and its associated cargo are trafficked to the cilia is unclear...
August 22, 2016: Human Molecular Genetics
Andrea Aguilar
No abstract text is available yet for this article.
September 2016: Nature Reviews. Nephrology
Wenyan Xu, Miaomiao Jin, Ruikun Hu, Hong Wang, Fan Zhang, Shiaulou Yuan, Ying Cao
Phosphoinositides, a family of phosphorylated derivatives of phosphatidylinositol (PtdIns), are tightly regulated both temporally and spatially by PtdIns phosphatases and kinases. Mutations in inositol polyphosphate 5-phosphatase E (INPP5E) cause Joubert syndrome, a human disorder associated with numerous ciliopathic defects, including renal cyst formation, linking phosphoinositides to ciliopathies. However, the molecular mechanism by which INPP5E-mediated PtdIns signaling regulates ciliogenesis and cystogenesis is unclear...
July 8, 2016: Journal of the American Society of Nephrology: JASN
Junya Hasegawa, Ryo Iwamoto, Takanobu Otomo, Akiko Nezu, Maho Hamasaki, Tamotsu Yoshimori
Autophagy is a multistep membrane traffic pathway. In contrast to autophagosome formation, the mechanisms underlying autophagosome-lysosome fusion remain largely unknown. Here, we describe a novel autophagy regulator, inositol polyphosphate-5-phosphatase E (INPP5E), involved in autophagosome-lysosome fusion process. In neuronal cells, INPP5E knockdown strongly inhibited autophagy by impairing the fusion step. A fraction of INPP5E is localized to lysosomes, and its membrane anchoring and enzymatic activity are necessary for autophagy...
September 1, 2016: EMBO Journal
Satria P Sajuthi, Neeraj K Sharma, Jeff W Chou, Nicholette D Palmer, David R McWilliams, John Beal, Mary E Comeau, Lijun Ma, Jorge Calles-Escandon, Jamehl Demons, Samantha Rogers, Kristina Cherry, Lata Menon, Ethel Kouba, Donna Davis, Marcie Burris, Sara J Byerly, Maggie C Y Ng, Nisa M Maruthur, Sanjay R Patel, Lawrence F Bielak, Leslie A Lange, Xiuqing Guo, Michèle M Sale, Kei Hang K Chan, Keri L Monda, Gary K Chen, Kira Taylor, Cameron Palmer, Todd L Edwards, Kari E North, Christopher A Haiman, Donald W Bowden, Barry I Freedman, Carl D Langefeld, Swapan K Das
Relative to European Americans, type 2 diabetes (T2D) is more prevalent in African Americans (AAs). Genetic variation may modulate transcript abundance in insulin-responsive tissues and contribute to risk; yet, published studies identifying expression quantitative trait loci (eQTLs) in African ancestry populations are restricted to blood cells. This study aims to develop a map of genetically regulated transcripts expressed in tissues important for glucose homeostasis in AAs, critical for identifying the genetic etiology of T2D and related traits...
August 2016: Human Genetics
Eyad Kalawy Fansa, Stefanie Kristine Kösling, Eldar Zent, Alfred Wittinghofer, Shehab Ismail
The phosphodiesterase 6 delta subunit (PDE6δ) shuttles several farnesylated cargos between membranes. The cargo sorting mechanism between cilia and other compartments is not understood. Here we show using the inositol polyphosphate 5'-phosphatase E (INPP5E) and the GTP-binding protein (Rheb) that cargo sorting depends on the affinity towards PDE6δ and the specificity of cargo release. High-affinity cargo is exclusively released by the ciliary transport regulator Arl3, while low-affinity cargo is released by Arl3 and its non-ciliary homologue Arl2...
2016: Nature Communications
Sandra Hakim, Jennifer M Dyson, Sandra J Feeney, Elizabeth M Davies, Absorn Sriratana, Monica N Koenig, Olga V Plotnikova, Ian M Smyth, Sharon D Ricardo, Robin M Hobbs, Christina A Mitchell
Polycystic kidney disease (PKD) is a common cause of renal failure with few effective treatments. INPP5E is an inositol polyphosphate 5-phosphatase that dephosphorylates phosphoinositide 3-kinase (PI3K)-generated PI(3,4,5)P3and is mutated in ciliopathy syndromes. GermlineInpp5edeletion is embryonically lethal, attributed to cilia stability defects, and is associated with polycystic kidneys. However, the molecular mechanisms responsible for PKD development uponInpp5eloss remain unknown. Here, we show conditional inactivation ofInpp5ein mouse kidney epithelium results in severe PKD and renal failure, associated with a partial reduction in cilia number and hyperactivation of PI3K/Akt and downstream mTORC1 signaling...
April 7, 2016: Human Molecular Genetics
Sarah Kittel-Schneider, Carina Lorenz, Joyce Auer, Lena Weißflog, Andreas Reif
BACKGROUND: DGKH is a replicated risk gene of bipolar disorder (BD). However, the pathophysiological role of the coded protein, diacylglycerol kinase eta, remains elusive. METHODS: In this proof-of-concept study we isolated mRNA from peripheral blood and fibroblasts of heterozygote DGKH risk variants carriers (risk haplotype rs994856/rs9525580/rs9525584 GAT) with bipolar disorder and non-risk variant carriers with and without bipolar disorder. Gene expression of DGKH1, DGKH2, INPP5E, PI4K2B, PIK4CA, PLCG2, PRKCA, PRKCD, PRKCE and PRKCH was analysed by qRT PCR...
July 1, 2016: Journal of Affective Disorders
Qingwen Xu, Yuxia Zhang, Qing Wei, Yan Huang, Jinghua Hu, Kun Ling
Defective primary cilia are causative to a wide spectrum of human genetic disorders, termed ciliopathies. Although the regulation of ciliogenesis is intensively studied, how it is initiated remains unclear. Here we show that type Iγ phosphatidylinositol 4-phosphate (PtdIns(4)P) 5-kinase (PIPKIγ) and inositol polyphosphate-5-phosphatase E (INPP5E), a Joubert syndrome protein, localize to the centrosome and coordinate the initiation of ciliogenesis. PIPKIγ counteracts INPP5E in regulating tau-tubulin kinase-2 (TTBK2) recruitment to the basal body, which promotes the removal of microtubule capping protein CP110 and the subsequent axoneme elongation...
2016: Nature Communications
Matthew J Eramo, Christina A Mitchell
The phosphoinositide 3-kinase (PI3K) generated lipid signals, PtdIns(3,4,5)P3 and PtdIns(3,4)P2, are both required for the maximal activation of the serine/threonine kinase proto-oncogene Akt. The inositol polyphosphate 5-phosphatases (5-phosphatases) hydrolyse the 5-position phosphate from the inositol head group of PtdIns(3,4,5)P3 to yield PtdIns(3,4)P2. Extensive work has revealed several 5-phosphatases inhibit PI3K-driven Akt signalling, by decreasing PtdIns(3,4,5)P3 despite increasing cellular levels of PtdIns(3,4)P2...
February 2016: Biochemical Society Transactions
Christin Hanke-Gogokhia, Zhijian Wu, Cecilia D Gerstner, Jeanne M Frederick, Houbin Zhang, Wolfgang Baehr
Arf-like protein 3 (ARL3) is a ubiquitous small GTPase expressed in ciliated cells of plants and animals. Germline deletion ofArl3in mice causes multiorgan ciliopathy reminiscent of Bardet-Biedl or Joubert syndromes. As photoreceptors are elegantly compartmentalized and have cilia, we probed the function of ARL3 (ADP-ribosylation factor (Arf)-like 3 protein) by generating rod photoreceptor-specific (prefix(rod)) and retina-specific (prefix(ret))Arl3deletions. In predegenerate(rod)Arl3(-/-)mice, lipidated phototransduction proteins showed trafficking deficiencies, consistent with the role of ARL3 as a cargo displacement factor for lipid-binding proteins...
March 25, 2016: Journal of Biological Chemistry
Jina Park, Nayoung Lee, Adriana Kavoussi, Jeong Taeg Seo, Chul Hoon Kim, Seok Jun Moon
Cilia are highly specialized antennae-like cellular organelles. Inositol polyphosphate 5-phosphatase E (INPP5E) converts PI(4,5)P2 into PI4P and is required for proper ciliary function. Although Inpp5e mutations are associated with ciliopathies in humans and mice, the precise molecular role INPP5E plays in cilia remains unclear. Here, we report that Drosophila INPP5E (dINPP5E) regulates ciliary protein trafficking by controlling the phosphoinositide composition of ciliary membranes. Mutations in dInpp5e lead to hearing deficits due to the mislocalization of dTULP and mechanotransduction channels, Inactive and NOMPC, in chordotonal cilia...
December 29, 2015: Cell Reports
Gisela G Slaats, Christine R Isabella, Hester Y Kroes, Jennifer C Dempsey, Hendrik Gremmels, Glen R Monroe, Ian G Phelps, Karen J Duran, Jonathan Adkins, Sairam A Kumar, Dana M Knutzen, Nine V Knoers, Nancy J Mendelsohn, David Neubauer, Sotiria D Mastroyianni, Julie Vogt, Lisa Worgan, Natalya Karp, Sarah Bowdin, Ian A Glass, Melissa A Parisi, Edgar A Otto, Colin A Johnson, Friedhelm Hildebrandt, Gijs van Haaften, Rachel H Giles, Dan Doherty
BACKGROUND: Joubert syndrome (JS) is a recessive ciliopathy characterised by a distinctive brain malformation 'the molar tooth sign'. Mutations in >27 genes cause JS, and mutations in 12 of these genes also cause Meckel-Gruber syndrome (MKS). The goals of this work are to describe the clinical features of MKS1-related JS and determine whether disease causing MKS1 mutations affect cellular phenotypes such as cilium number, length and protein content as potential mechanisms underlying JS...
January 2016: Journal of Medical Genetics
Francesc R Garcia-Gonzalo, Siew Cheng Phua, Elle C Roberson, Galo Garcia, Monika Abedin, Stéphane Schurmans, Takanari Inoue, Jeremy F Reiter
Primary cilia interpret vertebrate Hedgehog (Hh) signals. Why cilia are essential for signaling is unclear. One possibility is that some forms of signaling require a distinct membrane lipid composition, found at cilia. We found that the ciliary membrane contains a particular phosphoinositide, PI(4)P, whereas a different phosphoinositide, PI(4,5)P2, is restricted to the membrane of the ciliary base. This distribution is created by Inpp5e, a ciliary phosphoinositide 5-phosphatase. Without Inpp5e, ciliary PI(4,5)P2 levels are elevated and Hh signaling is disrupted...
August 24, 2015: Developmental Cell
Fubito Nakatsu
How phosphoinositide metabolism is coupled to primary cilia physiology is poorly understood. Reporting recently in Developmental Cell, Chávez et al. (2015) and Garcia-Gonzalo et al. (2015) show that INPP5E-mediated phosphoinositide metabolism, which creates a specific phosphoinositide distribution, ensures proper protein trafficking and Hh signaling in primary cilia.
August 24, 2015: Developmental Cell
Marcelo Chávez, Sabrina Ena, Jacqueline Van Sande, Alban de Kerchove d'Exaerde, Stéphane Schurmans, Serge N Schiffmann
Ciliary transport is required for ciliogenesis, signal transduction, and trafficking of receptors to the primary cilium. Mutations in inositol polyphosphate 5-phosphatase E (INPP5E) have been associated with ciliary dysfunction; however, its role in regulating ciliary phosphoinositides is unknown. Here we report that in neural stem cells, phosphatidylinositol 4-phosphate (PI4P) is found in high levels in cilia whereas phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P2) is not detectable. Upon INPP5E inactivation, PI(4,5)P2 accumulates at the ciliary tip whereas PI4P is depleted...
August 10, 2015: Developmental Cell
Yan Xu, Liping Guan, Xueshan Xiao, Jianguo Zhang, Shiqiang Li, Hui Jiang, Xiaoyun Jia, Jianhua Yang, Xiangming Guo, Ye Yin, Jun Wang, Qingjiong Zhang
PURPOSE: Mutations in 60 known genes were previously identified by exome sequencing in 79 of 157 families with retinitis pigmentosa (RP). This study analyzed variants in 129 genes associated with other forms of hereditary retinal dystrophy in the same cohort. METHODS: Apart from the 73 genes previously analyzed, a further 129 genes responsible for other forms of hereditary retinal dystrophy were selected based on RetNet. Variants in the 129 genes determined by whole exome sequencing were selected and filtered by bioinformatics analysis...
2015: Molecular Vision
Elle C Roberson, William E Dowdle, Aysegul Ozanturk, Francesc R Garcia-Gonzalo, Chunmei Li, Jan Halbritter, Nadia Elkhartoufi, Jonathan D Porath, Heidi Cope, Allison Ashley-Koch, Simon Gregory, Sophie Thomas, John A Sayer, Sophie Saunier, Edgar A Otto, Nicholas Katsanis, Erica E Davis, Tania Attié-Bitach, Friedhelm Hildebrandt, Michel R Leroux, Jeremy F Reiter
The Meckel syndrome (MKS) complex functions at the transition zone, located between the basal body and axoneme, to regulate the localization of ciliary membrane proteins. We investigated the role of Tmem231, a two-pass transmembrane protein, in MKS complex formation and function. Consistent with a role in transition zone function, mutation of mouse Tmem231 disrupts the localization of proteins including Arl13b and Inpp5e to cilia, resulting in phenotypes characteristic of MKS such as polydactyly and kidney cysts...
April 13, 2015: Journal of Cell Biology
Ferah Sönmez, Melike Güzünler-Şen, Dilek Yılmaz, Gamze Cömertpay, Marisol Heise, Sebahattin Çırak, Gökhan Uyanık
Joubert syndrome (JS) is an autosomal recessive genetic disorder. To date, mutations in 20 genes of the genetically heterogeneous JS and JS-related disorders (JSRD) have been reported. Renal involvement occurs in 2-20% of JS cases. Identified renal abnormalities are cystic dysplasia and nephronophthisis. Here we report the clinical course and management of renal failure in early childhood. We present two cases diagnosed with JS that developed end-stage renal disease at young ages. In the genetic studies, a c...
July 2014: Turkish Journal of Pediatrics
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"