A novel deletion mutation in the TUSC3 gene in a consanguineous Pakistani family with autosomal recessive nonsyndromic intellectual disability

<p>Abstract</p> <p>Background</p> <p>Intellectual disability (ID) is a serious disorder of the central nervous system with a prevalence of 1-3% in a general population. In the past decades, the research focus has been predominantly on X-linked ID (68 loci and 19 genes for non syndromic X linked ID) while for autosomal recessive nonsyndromic ID (NSID) only 30 loci and 6 genes have been reported to date.</p> <p>Methods</p> <p>Genome-wide homozygosity mapping with 500 K Nsp1 array (Affymetrix), CNV analysis, PCR based breakpoint mapping and DNA sequencing was performed to explore the genetic basis of autosomal recessive nonsyndromic ID in a large Pakistani family.</p> <p>Results</p> <p>Data analysis showed linkage at 8p23 locus with common homozygous region between SNPs rs6989820 and rs2237834, spanning a region of 12.494 Mb. The subsequent CNV analysis of the data revealed a homozygous deletion of 170.673 Kb which encompassed the <it>TUSC3 </it>gene.</p> <p>Conclusion</p> <p>We report a novel deletion mutation in <it>TUSC3 </it>gene which is the second gene after <it>TRAPPC9 </it>in which mutation has been identified in more than one family with autosomal recessive NSID. The study will aid in exploring the molecular pathway of cognition.</p

Integrated genome and transcriptome sequencing identifies a noncoding mutation in the genome replication factor DONSON as the cause of microcephaly-micromelia syndrome

While next-generation sequencing has accelerated the discovery of human disease genes, progress has been largely limited to the "low hanging fruit" of mutations with obvious exonic coding or canonical splice site impact. In contrast, the lack of high-throughput, unbiased approaches for functional assessment of most noncoding variants has bottlenecked gene discovery. We report the integration of transcriptome sequencing (RNA-seq), which surveys all mRNAs to reveal functional impacts of variants at the transcription level, into the gene discovery framework for a unique human disease, microcephaly-micromelia syndrome (MMS). MMS is an autosomal recessive condition described thus far in only a single First Nations population and causes intrauterine growth restriction, severe microcephaly, craniofacial anomalies, skeletal dysplasia, and neonatal lethality. Linkage analysis of affected families, including a very large pedigree, identified a single locus on Chromosome 21 linked to the disease (LOD > 9). Comprehensive genome sequencing did not reveal any pathogenic coding or canonical splicing mutations within the linkage region but identified several nonconserved noncoding variants. RNA-seq analysis detected aberrant splicing in DONSON due to one of these noncoding variants, showing a causative role for DONSON disruption in MMS. We show that DONSON is expressed in progenitor cells of embryonic human brain and other proliferating tissues, is co-expressed with components of the DNA replication machinery, and that Donson is essential for early embryonic development in mice as well, suggesting an essential conserved role for DONSON in the cell cycle. Our results demonstrate the utility of integrating transcriptomics into the study of human genetic disease when DNA sequencing alone is not sufficient to reveal the underlying pathogenic mutation

Previously described sequence variant in CDK5RAP2 gene in a Pakistani family with autosomal recessive primary microcephaly

<p>Abstract</p> <p>Background</p> <p>Autosomal Recessive Primary Microcephaly (MCPH) is a disorder of neurogenic mitosis. MCPH leads to reduced cerebral cortical volume and hence, reduced head circumference associated with mental retardation of variable degree. Genetic heterogeneity is well documented in patients with MCPH with six loci known, while pathogenic sequence variants in four respective genes have been identified so far. Mutations in <it>CDK5RAP2 </it>gene at MCPH3 locus have been least involved in causing MCPH phenotype.</p> <p>Methods</p> <p>All coding exons and exon/intron splice junctions of <it>CDK5RAP2 </it>gene were sequenced in affected and normal individuals of Pakistani MCPH family of Kashmiri origin, which showed linkage to MCPH3 locus on chromosome 9q33.2.</p> <p>Results</p> <p>A previously described nonsense mutation [243 T>A (S81X)] in exon 4 of <it>CDK5RAP2 </it>gene has been identified in the Pakistani family, presented here, with MCPH Phenotype. Genomic and cDNA sequence comparison revealed that the exact nomenclature for this mutation is 246 T>A (Y82X).</p> <p>Conclusion</p> <p>Recurrent observation of Y82X mutation in <it>CDK5RAP2 </it>gene in this Pakistani family may be a sign of confinement of a rare ancestral haplotype carrying this pathogenic variant within Northern Pakistani population, as this has not been reported in any other population.</p

The Adaptor Function of TRAPPC2 in Mammalian TRAPPs Explains TRAPPC2-Associated SEDT and TRAPPC9-Associated Congenital Intellectual Disability

Background: The TRAPP (Transport protein particle) complex is a conserved protein complex functioning at various steps in vesicle transport. Although yeast has three functionally and structurally distinct forms, TRAPPI, II and III, emerging evidence suggests that mammalian TRAPP complex may be different. Mutations in the TRAPP complex subunit 2 (TRAPPC2) cause X-linked spondyloepiphyseal dysplasia tarda, while mutations in the TRAPP complex subunit 9 (TRAPPC9) cause postnatal mental retardation with microcephaly. The structural interplay between these subunits found in mammalian equivalent of TRAPPI and those specific to TRAPPII and TRAPPIII remains largely unknown and we undertook the present study to examine the interaction between these subunits. Here, we reveal that the mammalian equivalent of the TRAPPII complex is structurally distinct from the yeast counterpart thus leading to insight into mechanism of disease. Principal Findings: We analyzed how TRAPPII- or TRAPPIII- specific subunits interact with the six-subunit core complex of TRAPP by co-immunoprecipitation in mammalian cells. TRAPPC2 binds to TRAPPII-specific subunit TRAPPC9, which in turn binds to TRAPPC10. Unexpectedly, TRAPPC2 can also bind to the putative TRAPPIII-specific subunit, TRAPPC8. Endogenous TRAPPC9-positive TRAPPII complex does not contain TRAPPC8, suggesting that TRAPPC2 binds to either TRAPPC9 or TRAPPC8 during the formation of the mammalian equivalents of TRAPPII or TRAPPIII, respectively. Therefore, TRAPPC2 serves as an adaptor for the formation of these complexes. A disease-causing mutation of TRAPPC2, D47Y, failed to interact with either TRAPPC9 or TRAPPC8, suggesting that aspartate 47 in TRAPPC2 is at or near the site of interaction with TRAPPC9 or TRAPPC8, mediating the formation of TRAPPII and/or TRAPPIII. Furthermore, disease-causing deletional mutants of TRAPPC9 all failed to interact with TRAPPC2 and TRAPPC10. Conclusions: TRAPPC2 serves as an adaptor for the formation of TRAPPII or TRAPPIII in mammalian cells. The mammalian equivalent of TRAPPII is likely different from the yeast TRAPPII structurally. © 2011 Zong et al.published_or_final_versio

Transcriptional Regulation Is a Major Controller of Cell Cycle Transition Dynamics

DNA replication, mitosis and mitotic exit are critical transitions of the cell cycle which normally occur only once per cycle. A universal control mechanism was proposed for the regulation of mitotic entry in which Cdk helps its own activation through two positive feedback loops. Recent discoveries in various organisms showed the importance of positive feedbacks in other transitions as well. Here we investigate if a universal control system with transcriptional regulation(s) and post-translational positive feedback(s) can be proposed for the regulation of all cell cycle transitions. Through computational modeling, we analyze the transition dynamics in all possible combinations of transcriptional and post-translational regulations. We find that some combinations lead to ‘sloppy’ transitions, while others give very precise control. The periodic transcriptional regulation through the activator or the inhibitor leads to radically different dynamics. Experimental evidence shows that in cell cycle transitions of organisms investigated for cell cycle dependent periodic transcription, only the inhibitor OR the activator is under cyclic control and never both of them. Based on these observations, we propose two transcriptional control modes of cell cycle regulation that either STOP or let the cycle GO in case of a transcriptional failure. We discuss the biological relevance of such differences

Endocytic regulation of alkali metal transport proteins in mammals, yeast and plants

The relative concentrations of ions and solutes inside cells are actively maintained by several classes of transport proteins, in many cases against their concentration gradient. These transport processes, which consume a large portion of cellular energy, must be constantly regulated. Many structurally distinct families of channels, carriers, and pumps have been characterized in considerable detail during the past decades and defects in the function of some of these proteins have been linked to a growing list of human diseases. The dynamic regulation of the transport proteins present at the cell surface is vital for both normal cellular function and for the successful adaptation to changing environments. The composition of proteins present at the cell surface is controlled on both the transcriptional and post-translational level. Post-translational regulation involves highly conserved mechanisms of phosphorylation- and ubiquitylation-dependent signal transduction routes used to modify the cohort of receptors and transport proteins present under any given circumstances. In this review, we will summarize what is currently known about one facet of this regulatory process: the endocytic regulation of alkali metal transport proteins. The physiological relevance, major contributors, parallels and missing pieces of the puzzle in mammals, yeast and plants will be discussed.This work was supported by grant BFU2011-30197-C03-03 from the Ministerio de Ciencia e Innovacion (Spain). V.L.-T. is supported by a fellowship from the Universidad Politecnica de Valencia. C. P. is supported by a fellowship from the Consejo Superior de Investigaciones Cientificas (Spain).Mulet Salort, JM.; Llopis Torregrosa, V.; Primo Planta, C.; Marques Romero, MC.; Yenush, L. (2013). Endocytic regulation of alkali metal transport proteins in mammals, yeast and plants. Current Genetics. 59(4):207-230. https://doi.org/10.1007/s00294-013-0401-2S207230594Abe F, Iida H (2003) Pressure-induced differential regulation of the two tryptophan permeases Tat1 and Tat2 by ubiquitin ligase Rsp5 and its binding proteins, Bul1 and Bul2. Mol Cell Biol 23:7566–7584Abriel H, Loffing J, Rebhun JF, Pratt JH, Schild L, Horisberger JD, Rotin D, Staub O (1999) Defective regulation of the epithelial Na+ channel by Nedd4 in Liddle’s syndrome. J Clin Invest 103:667–673. doi: 10.1172/JCI5713Alesutan I, Munoz C, Sopjani M, Dërmaku-Sopjani M, Michael D, Fraser S, Kemp BE, Seebohm G, Föller M, Lang F (2011) Inhibition of Kir2.1 (KCNJ2) by the AMP-activated protein kinase. Biochem Biophys Res Commun 408:505–510. doi: 10.1016/j.bbrc.2011.04.015Alvarez CE (2008) On the origins of arrestin and rhodopsin. BMC Evol Biol 8:222. doi: 10.1186/1471-2148-8-222Amerik AY, Nowak J, Swaminathan S, Hochstrasser M (2000) The Doa4 deubiquitinating enzyme is functionally linked to the vacuolar protein-sorting and endocytic pathways. Mol Biol Cell 11:3365–3380Anderson JA, Huprikar SS, Kochian LV, Lucas WJ, Gaber RF (1992) Functional expression of a probable Arabidopsis thaliana potassium channel in Saccharomyces cerevisiae. Proc Natl Acad Sci USA 89:3736–3740Anderson JA, Nakamura RL, Gaber RF (1994) Heterologous expression of K+ channels in Saccharomyces cerevisiae: strategies for molecular analysis of structure and function. Symp Soc Exp Biol 48:85–97Aniento F, Gu F, Parton RG, Gruenberg J (1996) An endosomal beta COP is involved in the pH-dependent formation of transport vesicles destined for late endosomes. J Cell Biol 133:29–41Apse MP, Aharon GS, Snedden WA, Blumwald E (1999) Salt tolerance conferred by overexpression of a vacuolar Na+/H+ antiport in Arabidopsis. Science 285:1256–1258Arino J, Ramos J, Sychrova H (2010) Alkali metal cation transport and homeostasis in yeasts. Microbiol mol biol rev 74:95–120. doi: 10.1128/mmbr.00042-09Arnason TG, Pisclevich MG, Dash MD, Davies GF, Harkness TA (2005) Novel interaction between Apc5p and Rsp5p in an intracellular signaling pathway in Saccharomyces cerevisiae. Eukaryot Cell 4:134–146. doi: 10.1128/EC.4.1.134-146.2005Arroyo JP, Lagnaz D, Ronzaud C, Vázquez N, Ko BS, Moddes L, Ruffieux-Daidié D, Hausel P, Koesters R, Yang B, Stokes JB, Hoover RS, Gamba G, Staub O (2011) Nedd4-2 modulates renal Na+ –Cl– cotransporter via the aldosterone-SGK1-Nedd4-2 pathway. J Am Soc Nephrol 22:1707–1719. doi: 10.1681/ASN.2011020132Azmi IF, Davies BA, Xiao J, Babst M, Xu Z, Katzmann DJ (2008) ESCRT-III family members stimulate Vps4 ATPase activity directly or via Vta1. Dev Cell 14:50–61. doi: 10.1016/j.devcel.2007.10.021Babst M, Katzmann DJ, Estepa-Sabal EJ, Meerloo T, Emr SD (2002a) Escrt-III: an endosome-associated heterooligomeric protein complex required for mvb sorting. Dev Cell 3:271–282Babst M, Katzmann DJ, Snyder WB, Wendland B, Emr SD (2002b) Endosome-associated complex, ESCRT-II, recruits transport machinery for protein sorting at the multivesicular body. Dev Cell 3:283–289Bache KG, Slagsvold T, Cabezas A, Rosendal KR, Raiborg C, Stenmark H (2004) The growth-regulatory protein HCRP1/hVps37A is a subunit of mammalian ESCRT-I and mediates receptor down-regulation. Mol Biol Cell 15:4337–4346. doi: 10.1091/mbc.E04-03-0250Baietti MF, Zhang Z, Mortier E, Melchior A, Degeest G, Geeraerts A, Ivarsson Y, Depoortere F, Coomans C, Vermeiren E, Zimmermann P, David G (2012) Syndecan-syntenin-ALIX regulates the biogenesis of exosomes. Nat Cell Biol 14:677–685. doi: 10.1038/ncb2502Barajas D, Nagy PD (2010) Ubiquitination of tombusvirus p33 replication protein plays a role in virus replication and binding to the host Vps23p ESCRT protein. Virology 397:358–368. doi: 10.1016/j.virol.2009.11.010Barajas D, Jiang Y, Nagy PD (2009) A unique role for the host ESCRT proteins in replication of Tomato bushy stunt virus. PLoS Pathog 5:e1000705. doi: 10.1371/journal.ppat.1000705Barberon M, Zelazny E, Robert S, Conéjéro G, Curie C, Friml J, Vert G (2011) Monoubiquitin-dependent endocytosis of the iron-regulated transporter 1 (IRT1) transporter controls iron uptake in plants. Proc Natl Acad Sci USA 108:E450–E458. doi: 10.1073/pnas.1100659108Barragán V, Leidi EO, Andrés Z, Rubio L, De Luca A, Fernández JA, Cubero B, Pardo JM (2012) Ion exchangers NHX1 and NHX2 mediate active potassium uptake into vacuoles to regulate cell turgor and stomatal function in Arabidopsis. Plant Cell 24:1127–1142. doi: 10.1105/tpc.111.095273Bassil E, Ohto MA, Esumi T, Tajima H, Zhu Z, Cagnac O, Belmonte M, Peleg Z, Yamaguchi T, Blumwald E (2011) The Arabidopsis intracellular Na+/H+ antiporters NHX5 and NHX6 are endosome associated and necessary for plant growth and development. Plant Cell 23:224–239. doi: 10.1105/tpc.110.079426Beaudenon SL, Huacani MR, Wang G, McDonnell DP, Huibregtse JM (1999) Rsp5 ubiquitin-protein ligase mediates DNA damage-induced degradation of the large subunit of RNA polymerase II in Saccharomyces cerevisiae. Mol Cell Biol 19:6972–6979Becuwe M, Vieira N, Lara D, Gomes-Rezende J, Soares-Cunha C, Casal M, Haguenauer-Tsapis R, Vincent O, Paiva S, Léon S (2012) A molecular switch on an arrestin-like protein relays glucose signaling to transporter endocytosis. J Cell Biol 196:247–259. doi: 10.1083/jcb.201109113Belgareh-Touzé N, Léon S, Erpapazoglou Z, Stawiecka-Mirota M, Urban-Grimal D, Haguenauer-Tsapis R (2008) Versatile role of the yeast ubiquitin ligase Rsp5p in intracellular trafficking. Biochem Soc Trans 36:791–796. doi: 10.1042/BST0360791Bhalla V, Oyster NM, Fitch AC, Wijngaarden MA, Neumann D, Schlattner U, Pearce D, Hallows KR (2006) AMP-activated kinase inhibits the epithelial Na+ channel through functional regulation of the ubiquitin ligase Nedd4-2. J Biol Chem 281:26159–26169. doi: 10.1074/jbc.M606045200Blondel MO, Morvan J, Dupre S, Urban-Grimal D, Haguenauer-Tsapis R, Volland C (2004) Direct sorting of the yeast uracil permease to the endosomal system is controlled by uracil binding and Rsp5p-dependent ubiquitylation. Mol Biol Cell 15:883–895. doi: 10.1091/mbc.E03-04-0202Boase NA, Rychkov GY, Townley SL, Dinudom A, Candi E, Voss AK, Tsoutsman T, Semsarian C, Melino G, Koentgen F, Cook DI, Kumar S (2011) Respiratory distress and perinatal lethality in Nedd4-2-deficient mice. Nat Commun 2:287. doi: 10.1038/ncomms1284Boehmer C, Laufer J, Jeyaraj S, Klaus F, Lindner R, Lang F, Palmada M (2008) Modulation of the voltage-gated potassium channel Kv1.5 by the SGK1 protein kinase involves inhibition of channel ubiquitination. Cell Physiol Biochem 22:591–600. doi: 10.1159/000185543Bonifacino JS, Traub LM (2003) Signals for sorting of transmembrane proteins to endosomes and lysosomes. Annu Rev Biochem 72:395–447. doi: 10.1146/annurev.biochem.72.121801.161800Bowers K, Levi BP, Patel FI, Stevens TH (2000) The sodium/proton exchanger Nhx1p is required for endosomal protein trafficking in the yeast Saccharomyces cerevisiae. Mol Biol Cell 11:4277–4294Brett CL, Tukaye DN, Mukherjee S, Rao R (2005) The yeast endosomal Na+K+/H+ exchanger Nhx1 regulates cellular pH to control vesicle trafficking. Mol Biol Cell 16:1396–1405. doi: 10.1091/mbc.E04-11-0999Cao XR, Lill NL, Boase N, Shi PP, Croucher DR, Shan H, Qu J, Sweezer EM, Place T, Kirby PA, Daly RJ, Kumar S, Yang B (2008) Nedd4 controls animal growth by regulating IGF-1 signaling. Sci Signal 1:ra5. doi: 10.1126/scisignal.1160940Carrasquillo R, Tian D, Krishna S, Pollak MR, Greka A, Schlöndorff J (2012) SNF8, a member of the ESCRT-II complex, interacts with TRPC6 and enhances its channel activity. BMC Cell Biol 13:33. doi: 10.1186/1471-2121-13-33Chen L, Hellmann H (2013) Plant E3 Ligases: flexible enzymes in a sessile world1. Mol Plant. doi: 10.1093/mp/sst005Chinchilla D, Zipfel C, Robatzek S, Kemmerling B, Nürnberger T, Jones JD, Felix G, Boller T (2007) A flagellin-induced complex of the receptor FLS2 and BAK1 initiates plant defence. Nature 448:497–500. doi: 10.1038/nature05999Christie KJ, Martinez JA, Zochodne DW (2012) Disruption of E3 ligase NEDD4 in peripheral neurons interrupts axon outgrowth: linkage to PTEN. Mol Cell Neurosci 50:179–192. doi: 10.1016/j.mcn.2012.04.006Clague MJ, Liu H, Urbé S (2012) Governance of endocytic trafficking and signaling by reversible ubiquitylation. Dev Cell 23:457–467. doi: 10.1016/j.devcel.2012.08.011Clancy JL, Henderson MJ, Russell AJ, Anderson DW, Bova RJ, Campbell IG, Choong DY, Macdonald GA, Mann GJ, Nolan T, Brady G, Olopade OI, Woollatt E, Davies MJ, Segara D, Hacker NF, Henshall SM, Sutherland RL, Watts CK (2003) EDD, the human orthologue of the hyperplastic discs tumour suppressor gene, is amplified and overexpressed in cancer. Oncogene 22:5070–5081. doi: 10.1038/sj.onc.1206775Coonrod EM, Stevens TH (2010) The yeast vps class E mutants: the beginning of the molecular genetic analysis of multivesicular body biogenesis. Mol Biol Cell 21:4057–4060. doi: 10.1091/mbc.E09-07-0603Crespo JL, Daicho K, Ushimaru T, Hall MN (2001) The GATA transcription factors GLN3 and GAT1 link TOR to salt stress in Saccharomyces cerevisiae. J Biol Chem 276:34441–34444. doi: 10.1074/jbc.M103601200Debonneville C, Flores SY, Kamynina E, Plant PJ, Tauxe C, Thomas MA, Münster C, Chraïbi A, Pratt JH, Horisberger JD, Pearce D, Loffing J, Staub O (2001) Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na(+) channel cell surface expression. EMBO J 20:7052–7059. doi: 10.1093/emboj/20.24.7052Downes BP, Stupar RM, Gingerich DJ, Vierstra RD (2003) The HECT ubiquitin-protein ligase (UPL) family in Arabidopsis: UPL3 has a specific role in trichome development. Plant J 35:729–742Eisenach C, Chen ZH, Grefen C, Blatt MR (2012) The trafficking protein SYP121 of Arabidopsis connects programmed stomatal closure and K+ channel activity with vegetative growth. Plant J 69:241–251. doi: 10.1111/j.1365-313X.2011.04786.xEkberg J, Schuetz F, Boase NA, Conroy SJ, Manning J, Kumar S, Poronnik P, Adams DJ (2007) Regulation of the voltage-gated K(+) channels KCNQ2/3 and KCNQ3/5 by ubiquitination. Novel role for Nedd4-2. J Biol Chem 282:12135–12142. doi: 10.1074/jbc.M609385200Faresse N, Lagnaz D, Debonneville A, Ismailji A, Maillard M, Fejes-Toth G, Náray-Fejes-Tóth A, Staub O (2012) Inducible kidney-specific Sgk1 knockout mice show a salt-losing phenotype. Am J Physiol Renal Physiol 302:F977–F985. doi: 10.1152/ajprenal.00535.2011Field MC, Gabernet-Castello C, Dacks JB (2007) Reconstructing the evolution of the endocytic system: insights from genomics and molecular cell biology. Adv Exp Med Biol 607:84–96. doi: 10.1007/978-0-387-74021-8_7Fisk HA, Yaffe MP (1999) A role for ubiquitination in mitochondrial inheritance in Saccharomyces cerevisiae. J Cell Biol 145:1199–1208Flinn RJ, Yan Y, Goswami S, Parker PJ, Backer JM (2010) The late endosome is essential for mTORC1 signaling. Mol Biol Cell 21:833–841. doi: 10.1091/mbc.E09-09-0756Fotia AB, Ekberg J, Adams DJ, Cook DI, Poronnik P, Kumar S (2004) Regulation of neuronal voltage-gated sodium channels by the ubiquitin-protein ligases Nedd4 and Nedd4-2. J Biol Chem 279:28930–28935. doi: 10.1074/jbc.M402820200Futter CE, White IJ (2007) Annexins and endocytosis. Traffic 8:951–958. doi: 10.1111/j.1600-0854.2007.00590.xGabriely G, Kama R, Gerst JE (2007) Involvement of specific COPI subunits in protein sorting from the late endosome to the vacuole in yeast. Mol Cell Biol 27:526–540. doi: 10.1128/MCB.00577-06Gajewska B, Shcherbik N, Oficjalska D, Haines DS, Zoladek T (2003) Functional analysis of the human orthologue of the RSP5-encoded ubiquitin protein ligase, hNedd4, in yeast. Curr Genet 43:1–10. doi: 10.1007/s00294-003-0371-xGalan JM, Moreau V, Andre B, Volland C, Haguenauer-Tsapis R (1996) Ubiquitination mediated by the Npi1p/Rsp5p ubiquitin-protein ligase is required for endocytosis of the yeast uracil permease. J Biol Chem 271:10946–10952Gao T, Liu Z, Wang Y, Cheng H, Yang Q, Guo A, Ren J, Xue Y (2013) UUCD: a family-based database of ubiquitin and ubiquitin-like conjugation. Nucleic Acids Res 41:D445–D451. doi: 10.1093/nar/gks1103Geldner N (2004) The plant endosomal system—its structure and role in signal transduction and plant development. Planta 219:547–560. doi: 10.1007/s00425-004-1302-xGitan RS, Eide DJ (2000) Zinc-regulated ubiquitin conjugation signals endocytosis of the yeast ZRT1 zinc transporter. Biochem J 346:329–336. doi: 10.1042/0264-6021:3460329Gitan RS, Luo H, Rodgers J, Broderius M, Eide D (1998) Zinc-induced inactivation of the yeast ZRT1 zinc transporter occurs through endocytosis and vacuolar degradation. J Biol Chem 273:28617–28624Gómez-Gómez L, Boller T (2000) FLS2: an LRR receptor-like kinase involved in the perception of the bacterial elicitor flagellin in Arabidopsis. Mol Cell 5:1003–1011Gong X, Chang A (2001) A mutant plasma membrane ATPase, Pma1-10, is defective in stability at the yeast cell surface. Proc Natl Acad Sci USA 98:9104–9109. doi: 10.1073/pnas.161282998Guo J, Wang T, Li X, Shallow H, Yang T, Li W, Xu J, Fridman MD, Yang X, Zhang S (2012) Cell surface expression of human ether-a-go–go-related gene (hERG) channels is regulated by caveolin-3 protein via the ubiquitin ligase Nedd4-2. J Biol Chem 287:33132–33141. doi: 10.1074/jbc.M112.389643Gwizdek C, Hobeika M, Kus B, Ossareh-Nazari B, Dargemont C, Rodriguez MS (2005) The mRNA nuclear export factor Hpr1 is regulated by Rsp5-mediated ubiquitylation. J Biol Chem 280:13401–13405. doi: 10.1074/jbc.C500040200Haas TJ, Sliwinski MK, Martínez DE, Preuss M, Ebine K, Ueda T, Nielsen E, Odorizzi G, Otegui MS (2007) The Arabidopsis AAA ATPase SKD1 is involved in multivesicular endosome function and interacts with its positive regulator LYST-INTERACTING PROTEIN5. Plant Cell 19:1295–1312. doi: 10.1105/tpc.106.049346Harkness TA, Davies GF, Ramaswamy V, Arnason TG (2002) The ubiquitin-dependent targeting pathway in Saccharomyces cerevisiae plays a critical role in multiple chromatin assembly regulatory steps. Genetics 162:615–632Hasenbrink G, Schwarzer S, Kolacna L, Ludwig J, Sychrova H, Lichtenberg-Fraté H (2005) Analysis of the mKir2.1 channel activity in potassium influx defective Saccharomyces cerevisiae strains determined as changes in growth characteristics. FEBS Lett 579:1723–1731. doi: 10.1016/j.febslet.2005.02.025Hatakeyama R, Kamiya M, Takahara T, Maeda T (2010) Endocytosis of the aspartic acid/glutamic acid transporter Dip5 is triggered by substrate-dependent recruitment of the Rsp5 ubiquitin ligase via the arrestin-like protein Aly2. Mol Cell Biol 30:5598–5607. doi: 10.1128/MCB.00464-10Hayashi M, Fukuzawa T, Sorimachi H, Maeda T (2005) Constitutive activation of the pH-responsive Rim101 pathway in yeast mutants defective in late steps of the MVB/ESCRT pathway. Mol Cell Biol 25:9478–9490. doi: 10.1128/mcb.25.21.9478-9490.2005He P, Lee SJ, Lin S, Seidler U, Lang F, Fejes-Toth G, Naray-Fejes-Toth A, Yun CC (2011) Serum- and glucocorticoid-induced kinase 3 in recycling endosomes mediates acute activation of Na+/H+ exchanger NHE3 by glucocorticoids. Mol Biol Cell 22:3812–3825. doi: 10.1091/mbc.E11-04-0328Heese A, Hann DR, Gimenez-Ibanez S, Jones AM, He K, Li J, Schroeder JI, Peck SC, Rathjen JP (2007) The receptor-like kinase SERK3/BAK1 is a central regulator of innate immunity in plants. Proc Natl Acad Sci USA 104:12217–12222. doi: 10.1073/pnas.0705306104Hein C, Springael JY, Volland C, Haguenauer-Tsapis R, André B (1995) NPl1, an essential yeast gene involved in induced degradation of Gap1 and Fur4 permeases, encodes the Rsp5 ubiquitin-protein ligase. Mol Microbiol 18:77–87Henke G, Maier G, Wallisch S, Boehmer C, Lang F (2004) Regulation of the voltage gated K+ channel Kv1.3 by the ubiquitin ligase Nedd4-2 and the serum and glucocorticoid inducible kinase SGK1. J Cell Physiol 199:194–199. doi: 10.1002/jcp.10430Herberth S, Shahriari M, Bruderek M, Hessner F, Müller B, Hülskamp M, Schellmann S (2012) Artificial ubiquitylation is sufficient for sorting of a plasma membrane ATPase to the vacuolar lumen of Arabidopsis cells. Planta 236:63–77. doi: 10.1007/s00425-012-1587-0Hicke L, Dunn R (2003) Regulation of membrane protein transport by ubiquitin and ubiquitin-binding proteins. Annu Rev Cell Dev Biol 19:141–172. doi: 10.1146/annurev.cellbio.19.110701.154617Hicke L, Riezman H (1996) Ubiquitination of a yeast plasma membrane receptor signals its ligand-stimulated endocytosis. Cell 84:277–287Hicke L, Zanolari B, Riezman H (1998) Cytoplasmic tail phosphorylation of the alpha-factor receptor is required for its ubiquitination and internalization. J Cell Biol 141:349–358Hoppe T, Matuschewski K, Rape M, Schlenker S, Ulrich HD, Jentsch S (2000) Activation of a membrane-bound transcription factor by regulated ubiquitin/proteasome-dependent processing. Cell 102:577–586Hsu C, Morohashi Y, Yoshimura S, Manrique-Hoyos N, Jung S, Lauterbach MA, Bakhti M, Grønborg M, Möbius W, Rhee J, Barr FA, Simons M (2010) Regulation of exosome secretion by Rab35 and its GTPase-activating proteins TBC1D10A-C. J Cell Biol 189:223–232. doi: 10.1083/jcb.200911018Hu G, Caza M, Cadieux B, Chan V, Liu V, Kronstad J (2013) Cryptococcus neoformans requires the ESCRT protein Vps23 for iron acquisition from heme, for capsule formation, and for virulence. Infect Immun 81:292–302. doi: 10.1128/IAI.01037-12Huang F, Kirkpatrick D, Jiang X, Gygi S, Sorkin A (2006) Differential regulation of EGF receptor internalization and degradation by multiubiquitination within the kinase domain. Mol Cell 21:737–748. doi: 10.1016/j.molcel.2006.02.018Huang F, Goh LK, Sorkin A (2007) EGF receptor ubiquitination is not necessary for its internalization. Proc Natl Acad Sci USA 104:16904–16909. doi: 10.1073/pnas.0707416104Huibregtse JM, Scheffner M, Beaudenon S, Howley PM (1995) A family of proteins structurally and functionally related to the E6-AP ubiquitin-protein ligase. Proc Natl Acad Sci USA 92:2563–2567Hurst AC, Meckel T, Tayefeh S, Thiel G, Homann U (2004) Trafficking of the plant potassium inward rectifier KAT1 in guard cell protoplasts of Vicia faba. Plant J 37:391–397Husnjak K, Dikic I (2012) Ubiquitin-binding proteins: decoders of ubiquitin-mediated cellular functions. Annu Rev Biochem 81:291–322. doi: 10.1146/annurev-biochem-051810-094654Ibl V, Csaszar E, Schlager N, Neubert S, Spitzer C, Hauser MT (2012) Interactome of the plant-specific ESCRT-III component AtVPS2.2 in Arabidopsis thaliana. J Proteome Res 11:397–411. doi: 10.1021/pr200845nIchimura T, Yamamura H, Sasamoto K, Tominaga Y, Taoka M, Kakiuchi K, Shinkawa T, Takahashi N, Shimada S, Isobe T (2005) 14-3-3 proteins modulate the expression of epithelial Na + channels by phosphorylation-dependent interaction with Nedd4-2 ubiquitin ligase. J Biol Chem 280:13187–13194. doi: 10.1074/jbc.M412884200Jegla TJ, Zmasek CM, Batalov S, Nayak SK (2009) Evolution of the human ion channel set. Comb Chem High Throughput Screen 12:2–23Jenness DD, Li Y, Tipper C, Spatrick P (1997) Elimination of defective alpha-factor pheromone receptors. Mol Cell Biol 17:6236–6245Jespersen T, Membrez M, Nicolas CS, Pitard B, Staub O, Olesen SP, Baró I, Abriel H (2007) The KCNQ1 potassium channel is down-regulated by ubiquitylating enzymes of the Nedd4/Nedd4-like family. Cardiovasc Res 74:64–74. doi: 10.1016/j.cardiores.2007.01.008Jolliffe CN, Harvey KF, Haines BP, Parasivam G, Kumar S (2000) Identification of multiple proteins expressed in murine embryos as binding partners for the WW domains of the ubiquitin-protein ligase Nedd4. Biochem J 351(Pt 3):557–565Kallay LM, Brett CL, Tukaye DN, Wemmer MA, Chyou A, Odorizzi G, Rao R (2011) Endosomal Na+(K+)/H+ exchanger Nhx1/Vps44 functions independently and downstream of multivesicular body formation. J Biol Chem 286:44067–44077. doi: 10.1074/jbc.M111.282319Kamsteeg EJ, Savelkoul PJ, Hendriks G, Konings IB, Nivillac NM, Lagendijk AK, van der Sluijs P, Deen PM (2008) Missorting of the Aquaporin-2 mutant E258K to multivesicular bodies/lysosomes in dominant NDI is associated with its monoubiquitination and increased phosphoryla