Gene Symbol: eff
Description: effete
Alias: 3527, 6535, CG7425, Dmel\CG7425, E(Pc)88D, EFF, Eff, SS3-3, UBC4, UBCD-1, UBCD1, Ubc-D1, UbcD, UbcD1, UbcH5, anon-WO0118547.343, fs(3)01295, l(3)01462, l(3)j2C8, l(3)s1782, mei68, ms(3)01295, ms(3)1, ms(3)3, ms(3)88D, ms(3)neo2, ms(3)ry1, ms(3)ry3, ubcD1, effete, CG7425-PA, CG7425-PB, CG7425-PC, eff-PA, eff-PB, eff-PC, effette, meiotic 68, suppressor of GMR-sina 3-3, ubiquitin conjugating enzyme 1
Species: fruit fly

Top Publications

  1. Raffa G, Ciapponi L, Cenci G, Gatti M. Terminin: a protein complex that mediates epigenetic maintenance of Drosophila telomeres. Nucleus. 2011;2:383-91 pubmed publisher
    ..Based on these findings, we propose that concomitant with telomerase loss Drosophila rapidly evolved terminin to bind chromosome ends in a sequence-independent fashion, and that terminin is functionally analogous to shelterin. ..
  2. Robertson H, Hime G, Lada H, Bowtell D. A Drosophila analogue of v-Cbl is a dominant-negative oncoprotein in vivo. Oncogene. 2000;19:3299-308 pubmed
  3. Lai E, Deblandre G, Kintner C, Rubin G. Drosophila neuralized is a ubiquitin ligase that promotes the internalization and degradation of delta. Dev Cell. 2001;1:783-94 pubmed
    ..Collectively, our data indicate that Neur is a ubiquitin ligase that positively regulates the N pathway by promoting the endocytosis and degradation of Dl...
  4. Ryoo H, Bergmann A, Gonen H, Ciechanover A, Steller H. Regulation of Drosophila IAP1 degradation and apoptosis by reaper and ubcD1. Nat Cell Biol. 2002;4:432-8 pubmed
    ..Drosophila melanogaster IAP1 (DIAP1) auto-ubiquitination and degradation is actively regulated by Reaper (Rpr) and UBCD1. We show that Rpr, but not Hid (head involution defective), promotes significant DIAP1 degradation...
  5. Cenci G, Ciapponi L, Gatti M. The mechanism of telomere protection: a comparison between Drosophila and humans. Chromosoma. 2005;114:135-45 pubmed
    ..Another telomere-protecting factor identified in Drosophila is UbcD1, a polypeptide highly homologous to class I ubiquitin-conjugating E2 enzymes...
  6. Cadavid A, Ginzel A, Fischer J. The function of the Drosophila fat facets deubiquitinating enzyme in limiting photoreceptor cell number is intimately associated with endocytosis. Development. 2000;127:1727-36 pubmed
    ..Moreover, it is demonstrated that the fat facets mutant phenotype is extraordinarily sensitive to the level of liquid facets expression. We propose that Liquid facets is a candidate for the critical substrate of Fat facets in the eye. ..
  7. Bergmann A, Yang A, Srivastava M. Regulators of IAP function: coming to grips with the grim reaper. Curr Opin Cell Biol. 2003;15:717-24 pubmed
    ..The apoptosis-inducing genes grim, reaper and hid modulate these mechanisms, and determine the outcome. ..
  8. Cenci G, Rawson R, Belloni G, Castrillon D, Tudor M, Petrucci R, et al. UbcD1, a Drosophila ubiquitin-conjugating enzyme required for proper telomere behavior. Genes Dev. 1997;11:863-75 pubmed
    ..We show here that five independent mutant alleles in the Drosophila UbcD1 gene cause frequent telomere-telomere attachments during both mitosis and male meiosis that are not seen in wild ..
  9. Michelle C, Vourc H P, Mignon L, Andres C. What was the set of ubiquitin and ubiquitin-like conjugating enzymes in the eukaryote common ancestor?. J Mol Evol. 2009;68:616-28 pubmed publisher
    ..A better understanding of the functions of these enzymes is necessary to decipher several human diseases. ..

More Information


  1. MusarĂ² M, Ciapponi L, Fasulo B, Gatti M, Cenci G. Unprotected Drosophila melanogaster telomeres activate the spindle assembly checkpoint. Nat Genet. 2008;40:362-6 pubmed publisher
    ..Our results collectively suggest that recruitment of BubR1 by dysfunctional telomeres inhibits Cdc20-APC function, preventing the metaphase-to-anaphase transition. ..
  2. Wu Z, Li Q, Fortini M, Fischer J. Genetic analysis of the role of the drosophila fat facets gene in the ubiquitin pathway. Dev Genet. 1999;25:312-20 pubmed
    ..the role of FAT FACETS in the ubiquitin pathway, genetic interactions between fat facets and the Drosophila UbcD1 gene were assessed...
  3. Fernandez Funez P, Nino Rosales M, de Gouyon B, She W, Luchak J, Martinez P, et al. Identification of genes that modify ataxin-1-induced neurodegeneration. Nature. 2000;408:101-6 pubmed
    ..These findings may be relevant to the treatment of polyglutamine diseases and, perhaps, to other neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. ..
  4. Cenci G, Ciapponi L, Marzullo M, Raffa G, Morciano P, Raimondo D, et al. The Analysis of Pendolino (peo) Mutants Reveals Differences in the Fusigenic Potential among Drosophila Telomeres. PLoS Genet. 2015;11:e1005260 pubmed publisher
    ..Alternatively, it is possible that Peo plays a dual function being independently required for DNA replication and telomere capping. ..
  5. Kramer H. Neuralized: regulating notch by putting away delta. Dev Cell. 2001;1:725-6 pubmed
    ..Neuralized acts in a subset of Notch-dependent cell fate decisions including lateral inhibition in Drosophila neurogenesis. Three recent papers reveal that Neuralized acts as a ubiquitin ligase and triggers endocytosis of the ligand Delta. ..
  6. Sameny A, Locke J. The P-element-induced silencing effect of KP transposons is dose dependent in Drosophila melanogaster. Genome. 2011;54:752-62 pubmed publisher
    ..A logarithmic dose dependency is consistent with the KP products interacting with heterochromatic proteins in a concentration-dependent manner such that two molecules are needed to induce gene silencing. ..
  7. Cipressa F, Romano S, Centonze S, zur Lage P, Vernì F, Dimitri P, et al. Effete, a Drosophila chromatin-associated ubiquitin-conjugating enzyme that affects telomeric and heterochromatic position effect variegation. Genetics. 2013;195:147-58 pubmed publisher
    ..Here, we show that with the exception of the effete (eff; also called UbcD1) mutant alleles, none of the tested mutations at the other telomere fusion genes affects ..
  8. Fauvarque M, Dura J. polyhomeotic regulatory sequences induce developmental regulator-dependent variegation and targeted P-element insertions in Drosophila. Genes Dev. 1993;7:1508-20 pubmed
    ..We suggest that a multimeric complex containing PH and PC proteins, at a minimum, causes a local and clonally inherited heterochromatinization, which maintains the repressed state of transcription of the homeotic genes. ..
  9. Asaoka T, Almagro J, Ehrhardt C, Tsai I, Schleiffer A, Deszcz L, et al. Linear ubiquitination by LUBEL has a role in Drosophila heat stress response. EMBO Rep. 2016;17:1624-1640 pubmed
    ..Thus, LUBEL is involved in the heat response by controlling linear ubiquitination in flies. ..
  10. Sandu C, Ryoo H, Steller H. Drosophila IAP antagonists form multimeric complexes to promote cell death. J Cell Biol. 2010;190:1039-52 pubmed publisher
    ..Both targeting of Rpr to mitochondria and forced dimerization strongly promotes apoptosis. Our results reveal the functional importance of a previously unrecognized multimeric IAP antagonist complex for the induction of apoptosis. ..
  11. Raffa G, Cenci G, Ciapponi L, Gatti M. Organization and Evolution of Drosophila Terminin: Similarities and Differences between Drosophila and Human Telomeres. Front Oncol. 2013;3:112 pubmed publisher
    ..Other proteins required to prevent end-to-end fusion in flies include HP1, Eff/UbcD1, ATM, the components of the Mre11-Rad50-Nbs (MRN) complex, and the Woc transcription factor...
  12. Ohlmeyer J, Schupbach T. Encore facilitates SCF-Ubiquitin-proteasome-dependent proteolysis during Drosophila oogenesis. Development. 2003;130:6339-49 pubmed
    ..Mutations in genes coding for components of the SCF pathway such as cul1, UbcD2 and effete enhance the extra division phenotype of encore...
  13. Lilly M, de Cuevas M, Spradling A. Cyclin A associates with the fusome during germline cyst formation in the Drosophila ovary. Dev Biol. 2000;218:53-63 pubmed
    ..Female sterile mutations in UbcD1, encoding an E2 ubiquitin-conjugating enzyme, have a similar effect...
  14. Carthew R, Xu C. Endocytosis: why not wait to deubiquitinate?. Curr Biol. 2000;10:R532-4 pubmed
    ..Surprisingly, this is the opposite effect that ubiquitination has on endocytosis of many plasma membrane proteins. ..
  15. Mathe E, Kraft C, Giet R, Deak P, Peters J, Glover D. The E2-C vihar is required for the correct spatiotemporal proteolysis of cyclin B and itself undergoes cyclical degradation. Curr Biol. 2004;14:1723-33 pubmed
    ..APC/C-mediated proteolysis of Vihar E2-C autoinactivates the APC/C at the centrosome before a second wave of proteolysis to degrade Cyclin B on the rest of the spindle and elsewhere in the cell. ..
  16. Palaga T, Osborne B. The 3D's of apoptosis: death, degradation and DIAPs. Nat Cell Biol. 2002;4:E149-51 pubmed
    ..Recent evidence suggests that in some situations, induction of apoptosis initiates general repression of translation, as well as the targeted ubiquitination and degradation of IAPs. ..
  17. Paquette N, Broemer M, Aggarwal K, Chen L, Husson M, Erturk Hasdemir D, et al. Caspase-mediated cleavage, IAP binding, and ubiquitination: linking three mechanisms crucial for Drosophila NF-kappaB signaling. Mol Cell. 2010;37:172-82 pubmed publisher
    ..Through its association with DIAP2, IMD is rapidly conjugated with K63-linked polyubiquitin chains. These results mechanistically connect caspase-mediated cleavage and K63 ubiquitination in immune-induced NF-kappaB signaling. ..
  18. Hans F, Fiesel F, Strong J, J ckel S, Rasse T, Geisler S, et al. UBE2E ubiquitin-conjugating enzymes and ubiquitin isopeptidase Y regulate TDP-43 protein ubiquitination. J Biol Chem. 2014;289:19164-79 pubmed publisher
    ..Thus, UBE2E3 and UBPY participate in the regulation of TDP-43 ubiquitination, solubility, and neurodegeneration...
  19. Matuschewski K, Hauser H, Treier M, Jentsch S. Identification of a novel family of ubiquitin-conjugating enzymes with distinct amino-terminal extensions. J Biol Chem. 1996;271:2789-94 pubmed
    ..In yeast, these enzymes can partially complement mutants deficient in the UBC4 E2 enzyme. This indicates that members of this novel E2 family may operate in UBC4-related proteolytic pathways.
  20. Chen X, Li Q, Fischer J. Genetic analysis of the Drosophila DNAprim gene. The function of the 60-kd primase subunit of DNA polymerase opposes the fat facets signaling pathway in the developing eye. Genetics. 2000;156:1787-95 pubmed
    ..Mechanisms by which DNA primase levels might influence the faf-dependent cell communication pathway are discussed. ..
  21. Bocca S, Muzzopappa M, Silberstein S, Wappner P. Occurrence of a putative SCF ubiquitin ligase complex in Drosophila. Biochem Biophys Res Commun. 2001;286:357-64 pubmed
    ..closest homologues to the human components of the SCF(betaTrCP) complex and the E2 ubiquitin-conjugating enzyme UbcH5. We show that putative Drosophila SCF core subunits dSkpA and dRbx1 both interact directly with dCu11 and the F-..
  22. Velentzas P, Velentzas A, Pantazi A, Mpakou V, Zervas C, Papassideri I, et al. Proteasome, but not autophagy, disruption results in severe eye and wing dysmorphia: a subunit- and regulator-dependent process in Drosophila. PLoS ONE. 2013;8:e80530 pubmed publisher
    ..proteasome components (Rpn1, Rpn2, ?5, ?5 and ?6) or distinct protein-ubiquitin conjugators (UbcD6, but not UbcD1 and UbcD4)...
  23. Hawley R. Unresolvable endings: defective telomeres and failed separation. Science. 1997;275:1441-3 pubmed
  24. Li S, Xu C, Carthew R. Phyllopod acts as an adaptor protein to link the sina ubiquitin ligase to the substrate protein tramtrack. Mol Cell Biol. 2002;22:6854-65 pubmed
    ..These results illustrate how Ras signaling can modulate an E3 ligase activity not by the phosphorylation of substrate proteins but by regulating the expression of specific E3 adaptors. ..
  25. Wing J, Schreader B, Yokokura T, Wang Y, Andrews P, Huseinovic N, et al. Drosophila Morgue is an F box/ubiquitin conjugase domain protein important for grim-reaper mediated apoptosis. Nat Cell Biol. 2002;4:451-6 pubmed
    ..Morgue may thus have a key function in apoptosis by targeting DIAP1 for ubiquitination and turnover. ..
  26. Mollaaghababa R, Sipos L, Tiong S, Papoulas O, Armstrong J, Tamkun J, et al. Mutations in Drosophila heat shock cognate 4 are enhancers of Polycomb. Proc Natl Acad Sci U S A. 2001;98:3958-63 pubmed
    ..HSC4 might be needed for the proper folding of a component of the Polycomb repression complex, or it may be a functional member of that complex...
  27. Yeh T, Bratton S. Caspase-dependent regulation of the ubiquitin-proteasome system through direct substrate targeting. Proc Natl Acad Sci U S A. 2013;110:14284-9 pubmed publisher
    ..Herein, we demonstrate that Grim self-associates in cells and is ubiquitinylated by DIAP1 at Lys136 in an UbcD1-dependent manner, resulting in its rapid turnover...
  28. Spradling A, Rubin G. Transposition of cloned P elements into Drosophila germ line chromosomes. Science. 1982;218:341-7 pubmed
    ..Thus P elements can efficiently and selectively transpose from extrachromosomal DNA to the DNA of germ line chromosomes in Drosophila embryos. These observations provide the basis for efficient DNA-mediated gene transfer in Drosophila. ..
  29. Wang P, Pai L. D-Cbl binding to Drk leads to dose-dependent down-regulation of EGFR signaling and increases receptor-ligand endocytosis. PLoS ONE. 2011;6:e17097 pubmed publisher
    ..The fusion proteins we developed may provide alternative strategies for therapy of cancers caused by hyper-activation of EGFR signaling. ..
  30. Cipressa F, Morciano P, Bosso G, Mannini L, Galati A, Raffa G, et al. A role for Separase in telomere protection. Nat Commun. 2016;7:10405 pubmed publisher
    ..Finally, we find that siRNA-induced depletion of ESPL1, the Sse human orthologue, causes telomere dysfunction and HP1 level reduction in primary fibroblasts, highlighting a conserved role of Separase in telomere protection. ..
  31. Xu D, Woodfield S, Lee T, Fan Y, Antonio C, Bergmann A. Genetic control of programmed cell death (apoptosis) in Drosophila. Fly (Austin). 2009;3:78-90 pubmed
    ..Here, we review the key players of the cell death pathway in Drosophila and discuss their roles in apoptotic and non-apoptotic processes. ..
  32. Lu Y, Wang F, Li Y, Ferris J, Lee J, Gao F. The Drosophila homologue of the Angelman syndrome ubiquitin ligase regulates the formation of terminal dendritic branches. Hum Mol Genet. 2009;18:454-62 pubmed publisher
    ..These findings suggest that dendritic pathology may contribute to neurological deficits in patients with Angelman syndrome. ..
  33. Kuo C, Zhu S, Younger S, Jan L, Jan Y. Identification of E2/E3 ubiquitinating enzymes and caspase activity regulating Drosophila sensory neuron dendrite pruning. Neuron. 2006;51:283-90 pubmed
    ..during metamorphosis, we conducted an E2/E3 ubiquitinating enzyme mutant screen, revealing that mutation in ubcD1, an E2 ubiquitin-conjugating enzyme, resulted in retention of C4da neuron dendrites during metamorphosis...
  34. Fauvarque M, Laurenti P, Boivin A, Bloyer S, Griffin Shea R, Bourbon H, et al. Dominant modifiers of the polyhomeotic extra-sex-combs phenotype induced by marked P element insertional mutagenesis in Drosophila. Genet Res. 2001;78:137-48 pubmed
    ..One such insertion enhanced the ph phenotype and we show that it is a new allele of UbcD1/eff, a gene encoding a ubiquitin-conjugating enzyme that is involved in telomere association and potentially in ..
  35. Martin S. Destabilizing influences in apoptosis: sowing the seeds of IAP destruction. Cell. 2002;109:793-6 pubmed
    ..Recent developments suggest that ubiquitin-proteasome mediated destruction of the Drosophila IAP, DIAP1, is a key event during the initiation of programmed cell death in the fly. ..
  36. Claveria C, Torres M. Mitochondrial apoptotic pathways induced by Drosophila programmed cell death regulators. Biochem Biophys Res Commun. 2003;304:531-7 pubmed
    ..Recent molecular and cellular analyses suggest, however, that the mechanisms of action of the main programmed cell death regulators in Drosophila include a canonical mitochondrial pathway. ..
  37. Philip A. Mitotic sister-chromatid separation: what Drosophila mutants can tell us. Trends Cell Biol. 1998;8:150 pubmed
  38. Chen D, Wang Q, Huang H, Xia L, Jiang X, Kan L, et al. Effete-mediated degradation of Cyclin A is essential for the maintenance of germline stem cells in Drosophila. Development. 2009;136:4133-42 pubmed publisher
    ..ubiquitin-dependent pathway mediated by the Drosophila eff gene, which encodes the E2 ubiquitin-conjugating enzyme Effete (Eff), plays an essential role in GSC maintenance...
  39. Li S, Wang C, Sandanaraj E, Aw S, Koe C, Wong J, et al. The SCFSlimb E3 ligase complex regulates asymmetric division to inhibit neuroblast overgrowth. EMBO Rep. 2014;15:165-74 pubmed publisher
    ..Moreover, Beta-transducin repeat containing, the human ortholog of Slimb, is frequently deleted in highly aggressive gliomas, suggesting a conserved tumor suppressor-like function. ..
  40. Caldwell J, Joiner M, Sivan Loukianova E, Eberl D. The role of the RING-finger protein Elfless in Drosophila spermatogenesis and apoptosis. Fly (Austin). 2008;2:269-79 pubmed
    ..key members of the apoptotic pathway including the initiator caspase Dronc and the ubiquitin conjugating enzyme UbcD1. DIAP1, but not UbcD1, protein levels are increased in heads of flies expressing Elfless-EGFP in the eye, and in ..
  41. Vandenabeele P, Bertrand M. The role of the IAP E3 ubiquitin ligases in regulating pattern-recognition receptor signalling. Nat Rev Immunol. 2012;12:833-44 pubmed publisher
    ..Understanding the role of IAPs in innate immunity may open new therapeutic perspectives for the treatment of PRR-dependent inflammatory diseases. ..
  42. Treier M, Seufert W, Jentsch S. Drosophila UbcD1 encodes a highly conserved ubiquitin-conjugating enzyme involved in selective protein degradation. EMBO J. 1992;11:367-72 pubmed
    ..We have cloned a gene from Drosophila melanogaster, UbcD1, coding for a protein with striking sequence similarity to the yeast ubiquitin-conjugating enzymes UBC4 and UBC5...
  43. Herman Bachinsky Y, Ryoo H, Ciechanover A, Gonen H. Regulation of the Drosophila ubiquitin ligase DIAP1 is mediated via several distinct ubiquitin system pathways. Cell Death Differ. 2007;14:861-71 pubmed
    ..Our preliminary data suggest that the autoubiquitination serves to attenuate the ligase activity of DIAP1 towards its exogenous substrates. ..
  44. Brachmann C, Cagan R. Patterning the fly eye: the role of apoptosis. Trends Genet. 2003;19:91-6 pubmed
    ..But, we have yet to understand how this signaling is regulated spatially to result in such precision. In this article, we describe and speculate on the role of selective cell death during maturation of the fly eye. ..
  45. Rumpf S, Bagley J, Thompson Peer K, Zhu S, Gorczyca D, Beckstead R, et al. Drosophila Valosin-Containing Protein is required for dendrite pruning through a regulatory role in mRNA metabolism. Proc Natl Acad Sci U S A. 2014;111:7331-6 pubmed publisher
    ..A similar combination of defects is also seen in a mutant in the ubiquitin-conjugating enzyme ubcD1 and a mutant in the 19S regulatory particle of the proteasome, but not in a 20S proteasome mutant...
  46. Ditzel M, Broemer M, Tenev T, Bolduc C, Lee T, Rigbolt K, et al. Inactivation of effector caspases through nondegradative polyubiquitylation. Mol Cell. 2008;32:540-53 pubmed publisher
    ..Taken together, our findings demonstrate that effector caspases regulate their own inhibition through a negative feedback mechanism involving DIAP1 "activation" and nondegradative polyubiquitylation. ..
  47. Lilly M, Spradling A. The Drosophila endocycle is controlled by Cyclin E and lacks a checkpoint ensuring S-phase completion. Genes Dev. 1996;10:2514-26 pubmed
    ..Unexpectedly, two to three of the 16 cells in cycE01672 cysts frequently differentiate as oocytes, implicating cell-cycle programming in oocyte determination. ..
  48. Watts R, Hoopfer E, Luo L. Axon pruning during Drosophila metamorphosis: evidence for local degeneration and requirement of the ubiquitin-proteasome system. Neuron. 2003;38:871-85 pubmed
    ..Our findings suggest that some forms of axon pruning during development may share similarities with degeneration of axons in response to injury. ..
  49. Cenci G, Siriaco G, Gatti M. The role of HeT-A and TART retrotransposons in Drosophila telomere capping. Genetica. 2003;117:311-8 pubmed
    ..the role of these sequences in the formation of telomere-telomere attachments induced by mutations in the UbcD1 gene...
  50. Park E, Elangovan M, Kim Y, Yoo Y. UbcD4, an ortholog of E2-25K/Ube2K, is essential for activation of the immune deficiency pathway in Drosophila. Biochem Biophys Res Commun. 2016;469:891-6 pubmed publisher
    ..We found that UbcD4, in addition to the previously reported E2s Effete and Bendless, was required for activation of the IMD pathway...
  51. Yoo S. Grim stimulates Diap1 poly-ubiquitination by binding to UbcD1. Mol Cells. 2005;20:446-51 pubmed
    ..We found that Grim stimulates poly-ubiquitination of Diap1 in the presence of UbcD1 and that it binds to UbcD1 in a GST pull-down assay, so presumably promoting Diap1 degradation...
  52. Neufeld T, Tang A, Rubin G. A genetic screen to identify components of the sina signaling pathway in Drosophila eye development. Genetics. 1998;148:277-86 pubmed
    ..of this phenotype identified mutations in a number of genes required for normal eye development, including UbcD1, which encodes a ubiquitin conjugating enzyme; SR3-4a, a gene previously implicated in signaling downstream of ..
  53. Oh C, McMahon R, Benzer S, Tanouye M. bendless, a Drosophila gene affecting neuronal connectivity, encodes a ubiquitin-conjugating enzyme homolog. J Neurosci. 1994;14:3166-79 pubmed
    ..The major role of ubiquitination in the protein degradative pathway suggests that ben regulates neural developmental processes such as growth cone guidance by targeting specific proteins for degradation. ..
  54. Tang A, Neufeld T, Kwan E, Rubin G. PHYL acts to down-regulate TTK88, a transcriptional repressor of neuronal cell fates, by a SINA-dependent mechanism. Cell. 1997;90:459-67 pubmed
    ..evidence that SINA, PHYL, and TTK88 physically interact and that SINA interacts genetically and physically with UBCD1, a component of the ubiquitin-dependent protein degradation pathway...
  55. Biessmann H, Mason J. Telomerase-independent mechanisms of telomere elongation. Cell Mol Life Sci. 2003;60:2325-33 pubmed
    ..We will summarize current knowledge on these telomerase-independent elongation mechanisms in yeast and mammalian cells and will discuss in more detail the telomere elongation mechanism by retrotransposons in Drosophila melanogaster. ..
  56. Danial N, Korsmeyer S. Cell death: critical control points. Cell. 2004;116:205-19 pubmed
    ..The identification of critical control points in the cell death pathway has yielded fundamental insights for basic biology, as well as provided rational targets for new therapeutics. ..