Fig4 Explained
Polyphosphoinositide phosphatase also known as phosphatidylinositol 3,5-bisphosphate 5-phosphatase or SAC domain-containing protein 3 (Sac3) is an enzyme that in humans is encoded by the FIG4 gene.[1] Fig4 is an abbreviation for Factor-Induced Gene.[2]
Function
Sac3 protein belongs to a family of human phosphoinositide phosphatases containing a Sac1-homology domain. The Sac1 phosphatase domain encompasses approximately 400 amino acids and consists of seven conserved motifs. It harbors the signature CX5R (T/S) catalytic sequence also found in other lipid and protein tyrosine phosphatases.[3] The founding protein, containing this evolutionarily-conserved domain, has been the first gene product isolated in a screen for Suppressors of yeast ACtin mutations and therefore named Sac1.[4] There are 5 human genes containing a Sac1 domain. Three of these genes (gene symbols SACM1L, INPP5F and FIG4), harbor a single Sac1 domain.[5] In the other two genes, synaptojanin 1 and 2, the Sac1 domain coexists with another phosphoinositide phosphatase domain, with both domains supporting phosphate hydrolysis.[6] [7] [8] In humans, the FIG4 gene localizes on chromosome 6 and encodes a Sac3 protein of 907 amino acids.[9] Sac3 is characterized as a widespread 97-kDa protein that, in in vitro assays, displays phosphatase activity towards a range of 5’-phosphorylated phosphoinositides.[10] [11] Sac3 forms a hetero-oligomer with ArPIKfyve (gene symbol, VAC14) and this binary complex associates with the phosphoinositide kinase PIKFYVE in a ternary PAS complex (from the first letters of PIKfyve-ArPIKfyve-Sac3), which is required to maintain proper endosomal membrane dynamics.[12] [13] This unique physical association of two enzymes with opposing functions leads to activation of the phosphoinositide kinase PIKfyve and increases of PIKfyve-catalized PtdIns(3,5)P2 and PtdIns5P production. Sac3 is active as a phosphatase in the triple complex and is responsible for turning over PtdIns(3,5)P2 to PtdIns3P.[12] [13] The PAS complex function is critical for life, because the knockout of each of the 3 genes encoding the PIKfyve, ArPIKfyve or Sac3 protein causes early embryonic,[14] perinatal,[15] or early juvenile lethality[16] in mice.Ectopically expressed Sac3 protein has a very short half-life of only ~18 min due to fast degradation in the proteasome. Co-expression of ArPIKfyve markedly prolongs Sac3 half-life, whereas siRNA-mediated ArPIKfyve knockdown profoundly reduces Sac3 levels. Thus, the Sac3 cellular levels are critically dependent on Sac3 physical interaction with ArPIKfyve.[12] [17] The C-terminal part of Sac3 is essential for this interaction. Insulin treatment of 3T3L1 adipocytes inhibits the Sac3 phosphatase activity as measured in vitro. Small interfering RNA-mediated knockdown of endogenous Sac3 by ~60%, resulting in a slight but significant elevation of PtdIns(3,5)P2 in 3T3L1 adipocytes, increases GLUT4 translocation and glucose uptake in response to insulin. In contrast, ectopic expression of Sac3, but not that of a phosphatase-deficient point-mutant, decreases GLUT4 plasma membrane abundance in response to insulin. Thus, Sac3 is an insulin-sensitive lipid phosphatase whose down-regulation improves insulin responsiveness.[18]
Medical significance
Mutations in the FIG4 gene cause a rare autosomal recessive Charcot-Marie-Tooth peripheral neuropathy type 4J (CMT4J).[16] Most CMT4J patients (15 out of the reported 16) are compound heterozygotes, i.e., the one FIG4 allele is null whereas the other encodes a mutant protein with threonine for isoleucine substitution at position 41.[19] The Sac3I41T point mutation abrogates the protective action of ArPIKfyve on Sac3 half-life. As a result mutant Sac3 is rapidly degraded in the proteasome.[17] Consequently, the Sac3I41T protein level in patient fibroblasts is from very low to undetectable.[20] [21] Clinically, the onset and severity of CMT4J symptoms vary markedly, suggesting an important role of genetic background in the individual course of disease.[21] In two siblings, with severe peripheral motor deficits and moderate sensory symptoms, the disease had relatively little impact on the central nervous system.[22] Phosphoinositide profiling in fibroblasts derived from the largest CMT4J cohort reported in USA thus far reveals decreased steady-state levels of both PtdIns(3,5)P2 and PtdIns5P. This unexpected direction of the changes is a result of impaired activation of the PIKFYVE kinase under the condition of Sac3 protein deficiency and a failure of the PAS complex assembly.[23] The reduction in PtdIns(3,5)P2 and PtdIns5P levels is reportedly unrelated to gender or the disease onset, suggesting that the pathological decline in levels of the two lipids might precede the disease symptoms.[23] FIG4 mutations are also found (without proven causation) in patients with amyotrophic lateral sclerosis (ALS)[24] as well as in other spectrum of phenotypes such as Yunis-Varon syndrome, cortical malformation with seizures and psychiatric co-morbidities, and cerebral hypomyelination.
Mouse models
Spontaneous FIG4 knockout leads to mutant mice with smaller size, selectively reduced PtdIns(3,5)P2 levels in isolated fibroblasts, diluted pigmentation, central and peripheral neurodegeneration, hydrocephalus, abnormal tremor and gait, and eventually juvenile lethality, hence the name pale tremor mouse (plt).[16] [20] Neuronal autophagy has been suggested as an important consequence of the knockout,[25] however, its primary relevance is disputed.[26] The plt mice show distinct morphological defects in motor and central neurons on the one hand, and sensory neurons - on the other.[26] Transgenic mice with one spontaneously null allele and another encoding several copies of mouse Sac3I41T mutant (i.e., the genotypic equivalent of human CMT4J), are dose-dependently rescued from the lethality, neurodegeneration, and brain apoptosis observed in the plt mice. However, the hydrocephalus and diluted pigmentation seen in plt mice are not corrected.[20]
Evolutionary biology
Genes encoding orthologs of human Sac3 are found in all eukaryotes. The most studied is the S. cerevisiae gene, discovered in a screen for yeast pheromone (Factor)-Induced Genes, hence the name Fig, with the number 4 reflecting the serendipity of isolation.[27] Yeast Fig4p is a specific PtdIns(3,5)P2 5’-phosphatase, which physically interacts with Vac14p (the ortholog of human ArPIKfyve),[28] and the PtdIns(3,5)P2-producing enzyme Fab1p (the ortholog of PIKfyve).[29] The yeast Fab1p-Vac14p-Fig4p complex also involves Vac7p and potentially Atg18p.[30] Deletion of Fig4p in budding yeast has relatively little effect on growth, basal PtdIns(3,5)P2 levels and the vacuolar size in comparison with the deletions of Vac14p or Fab1p.[31] In brief, in evolution Sac3/Fig4 retained the Sac1 domain, phosphoinositide phosphatase activity, and the protein interactions from yeast. In mice, the protein is essential in early postnatal development. In humans, its I41T point mutation in combination with a null allele causes a neurodegenerative disorder.
Further reading
- Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. . Gene. 138 . 1–2 . 171–4 . 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library. . Gene. 200 . 1–2 . 149–56 . 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 . etal.
- Strausberg RL, Feingold EA, Grouse LH . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. . Proceedings of the National Academy of Sciences. 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . etal. free .
- Zhong R, Ye ZH . The SAC domain-containing protein gene family in Arabidopsis. . Plant Physiology. 132 . 2 . 544–55 . 2003 . 12805586 . 10.1104/pp.103.021444 . 166996 .
- Mungall AJ, Palmer SA, Sims SK . The DNA sequence and analysis of human chromosome 6. . Nature. 425 . 6960 . 805–11 . 2003 . 14574404 . 10.1038/nature02055 . 2003Natur.425..805M . etal. free .
- Gerhard DS, Wagner L, Feingold EA . The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). . Genome Research. 14 . 10B . 2121–7 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 . etal.
External links
Notes and References
- Web site: Entrez Gene: FIG4 FIG4 homolog, SAC1 lipid phosphatase domain containing (S. cerevisiae).
- Erdman S, Lin L, Malczynski M, Snyder M . Pheromone-regulated genes required for yeast mating differentiation . Journal of Cell Biology. 140 . 3 . 461–83 . February 1998 . 9456310 . 2140177 . 10.1083/jcb.140.3.461.
- Hughes WE, Cooke FT, Parker PJ . Sep 2000 . Sac phosphatase domain proteins . Biochemical Journal. 350 . 2. 337–52 . 10947947 . 1221260 . 10.1042/0264-6021:3500337 .
- Novick P, Osmond BC, Botstein D . Apr 1989 . Suppressors of yeast actin mutations . Genetics. 121 . 4. 659–74 . 10.1093/genetics/121.4.659 . 2656401 . 1203651 .
- Minagawa T, Ijuin T, Mochizuki Y, Takenawa T . Jun 2001 . Identification and characterization of a sac domain-containing phosphoinositide 5-phosphatase . Journal of Biological Chemistry. 276 . 25. 22011–5 . 11274189 . 10.1074/jbc.M101579200 . free .
- Majerus PW, York JD . Apr 2009 . Phosphoinositide phosphatases and disease . Journal of Lipid Research. 50 . Suppl . S249–54 . 19001665 . 10.1194/jlr.R800072-JLR200 . free . 2674710 .
- Sasaki T, Takasuga S, Sasaki J, Kofuji S, Eguchi S, Yamazaki M, Suzuki A . Nov 2009 . Mammalian phosphoinositide kinases and phosphatases . Progress in Lipid Research. 48 . 6. 307–43 . 19580826 . 10.1016/j.plipres.2009.06.001 .
- Liu Y, Bankaitis VA . Jul 2010 . Phosphoinositide phosphatases in cell biology and disease . Progress in Lipid Research. 49 . 3. 201–17 . 20043944 . 10.1016/j.plipres.2009.12.001 . 2873057 .
- Nagase T, Seki N, Ishikawa K, Ohira M, Kawarabayasi Y, Ohara O, Tanaka A, Kotani H, Miyajima N, Nomura N . Oct 1996 . Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain . DNA Research. 3 . 5. 321–9, 341–54 . 9039502 . 10.1093/dnares/3.5.321 . free .
- Sbrissa D, Ikonomov OC, Fu Z, Ijuin T, Gruenberg J, Takenawa T, Shisheva A . Aug 2007 . Core protein machinery for mammalian phosphatidylinositol 3,5-bisphosphate synthesis and turnover that regulates the progression of endosomal transport. Novel Sac phosphatase joins the ArPIKfyve-PIKfyve complex . The Journal of Biological Chemistry. 282 . 33. 23878–91 . 17556371 . 10.1074/jbc.M611678200 . free .
- Yuan Y, Gao X, Guo N, Zhang H, Xie Z, Jin M, Li B, Yu L, Jing N . Nov 2007 . rSac3, a novel Sac domain phosphoinositide phosphatase, promotes neurite outgrowth in PC12 cells . Cell Research. 17 . 11. 919–32 . 17909536 . 10.1038/cr.2007.82 . free .
- Sbrissa D, Ikonomov OC, Fenner H, Shisheva A . Dec 2008 . ArPIKfyve homomeric and heteromeric interactions scaffold PIKfyve and Sac3 in a complex to promote PIKfyve activity and functionality . Journal of Molecular Biology. 384 . 4. 766–79 . 18950639 . 10.1016/j.jmb.2008.10.009 . 2756758 .
- Ikonomov OC, Sbrissa D, Fenner H, Shisheva A . Dec 2009 . PIKfyve-ArPIKfyve-Sac3 core complex: contact sites and their consequence for Sac3 phosphatase activity and endocytic membrane homeostasis . The Journal of Biological Chemistry. 284 . 51. 35794–806 . 19840946 . 10.1074/jbc.M109.037515 . 2791009 . free .
- Ikonomov OC, Sbrissa D, Delvecchio K, Xie Y, Jin JP, Rappolee D, Shisheva A . Apr 2011 . The phosphoinositide kinase PIKfyve is vital in early embryonic development: preimplantation lethality of PIKfyve-/- embryos but normality of PIKfyve+/- mice . The Journal of Biological Chemistry. 286 . 15. 13404–13 . 21349843 . 10.1074/jbc.M111.222364 . 3075686 . free .
- Zhang Y, Zolov SN, Chow CY, Slutsky SG, Richardson SC, Piper RC, Yang B, Nau JJ, Westrick RJ, Morrison SJ, Meisler MH, Weisman LS . Oct 2007 . Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results in neurodegeneration in mice . Proceedings of the National Academy of Sciences. 104 . 44. 17518–23 . 17956977 . 10.1073/pnas.0702275104 . 2077288 . 2007PNAS..10417518Z . free .
- Chow CY, Zhang Y, Dowling JJ, Jin N, Adamska M, Shiga K, Szigeti K, Shy ME, Li J, Zhang X, Lupski JR, Weisman LS, Meisler MH . Jul 2007 . Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J . Nature. 448 . 7149. 68–72 . 17572665 . 10.1038/nature05876 . 2271033 . 2007Natur.448...68C .
- Ikonomov OC, Sbrissa D, Fligger J, Delvecchio K, Shisheva A . Aug 2010 . ArPIKfyve regulates Sac3 protein abundance and turnover: disruption of the mechanism by Sac3I41T mutation causing Charcot-Marie-Tooth 4J disorder . The Journal of Biological Chemistry. 285 . 35. 26760–4 . 20630877 . 10.1074/jbc.C110.154658 . 2930674 . free .
- Ikonomov OC, Sbrissa D, Ijuin T, Takenawa T, Shisheva A . Sep 2009 . Sac3 is an insulin-regulated phosphatidylinositol 3,5-bisphosphate phosphatase: gain in insulin responsiveness through Sac3 down-regulation in adipocytes . The Journal of Biological Chemistry. 284 . 36. 23961–71 . 19578118 . 10.1074/jbc.M109.025361 . 2781990 . free .
- Nicholson G, Lenk GM, Reddel SW, Grant AE, Towne CF, Ferguson CJ, Simpson E, Scheuerle A, Yasick M, Hoffman S, Blouin R, Brandt C, Coppola G, Biesecker LG, Batish SD, Meisler MH . Jul 2011 . Distinctive genetic and clinical features of CMT4J: a severe neuropathy caused by mutations in the PI(3,5)P2 phosphatase FIG4 . Brain. 134 . 7. 1959–71 . 21705420 . 10.1093/brain/awr148 . 3122378 .
- Lenk GM, Ferguson CJ, Chow CY, Jin N, Jones JM, Grant AE, Zolov SN, Winters JJ, Giger RJ, Dowling JJ, Weisman LS, Meisler MH . Jun 2011 . Pathogenic mechanism of the FIG4 mutation responsible for Charcot-Marie-Tooth disease CMT4J . PLOS Genetics. 7 . 6. e1002104 . 21655088 . 10.1371/journal.pgen.1002104 . 3107197 . free .
- Hu B, McCollum M, Ravi V, Arpag S, Moiseev D, Castoro R, Mobley B, Burnette B, Suskind C, Day J, Yawn R, Feely S, Li Y, Yan Q, Shy M, Li J . Apr 2018 . Myelin abnormality in Charcot-Marie-Tooth type 4J recapitulates features of acquired demyelination . Annals of Neurology . 83 . 4 . 756–770 . 29518270 . 10.1002/ana.25198 . 5912982 .
- Zhang X, Chow CY, Sahenk Z, Shy ME, Meisler MH, Li J . Aug 2008 . Mutation of FIG4 causes a rapidly progressive, asymmetric neuronal degeneration . Brain. 131 . 8. 1990–2001 . 18556664 . 10.1093/brain/awn114 . 2724900 .
- Shisheva A, Sbrissa D, Hu B, Li J . Dec 2019 . Severe Consequences of SAC3/FIG4 Phosphatase Deficiency to Phosphoinositides in Patients with Charcot-Marie-Tooth Disease Type-4J . Molecular Neurobiology . 56 . 12 . 8656–67 . 10.1007/s12035-019-01693-8 . 31313076 . 197423698 .
- Chow CY, Landers JE, Bergren SK, Sapp PC, Grant AE, Jones JM, Everett L, Lenk GM, McKenna-Yasek DM, Weisman LS, Figlewicz D, Brown RH, Meisler MH . Jan 2009 . Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS . The American Journal of Human Genetics. 84 . 1. 85–8 . 19118816 . 10.1016/j.ajhg.2008.12.010 . 2668033 .
- Ferguson CJ, Lenk GM, Meisler MH . Dec 2009 . Defective autophagy in neurons and astrocytes from mice deficient in PI(3,5)P2 . Human Molecular Genetics. 18 . 24. 4868–78 . 19793721 . 10.1093/hmg/ddp460 . 2778378 .
- Katona I, Zhang X, Bai Y, Shy ME, Guo J, Yan Q, Hatfield J, Kupsky WJ, Li J . Apr 2011 . Distinct pathogenic processes between Fig4-deficient motor and sensory neurons . European Journal of Neuroscience. 33 . 8. 1401–10 . 10.1111/j.1460-9568.2011.07651.x . 21410794 . 24916509 .
- Erdman S, Lin L, Malczynski M, Snyder M . Feb 1998 . Pheromone-regulated genes required for yeast mating differentiation . Journal of Cell Biology. 140 . 3. 461–83 . 9456310 . 2140177 . 10.1083/jcb.140.3.461 .
- Rudge SA, Anderson DM, Emr SD . Jan 2004 . Vacuole size control: regulation of PtdIns(3,5)P2 levels by the vacuole-associated Vac14-Fig4 complex, a PtdIns(3,5)P2-specific phosphatase . Molecular Biology of the Cell. 15 . 1. 24–36 . 14528018 . 10.1091/mbc.E03-05-0297 . 307524 .
- Botelho RJ, Efe JA, Teis D, Emr SD . Oct 2008 . Assembly of a Fab1 phosphoinositide kinase signaling complex requires the Fig4 phosphoinositide phosphatase . Molecular Biology of the Cell. 19 . 10. 4273–86 . 18653468 . 10.1091/mbc.E08-04-0405 . 2555960 .
- Jin N, Chow CY, Liu L, Zolov SN, Bronson R, Davisson M, Petersen JL, Zhang Y, Park S, Duex JE, Goldowitz D, Meisler MH, Weisman LS . Dec 2008 . VAC14 nucleates a protein complex essential for the acute interconversion of PI3P and PI(3,5)P(2) in yeast and mouse . The EMBO Journal. 27 . 24. 3221–34 . 19037259 . 10.1038/emboj.2008.248 . 2600653 .
- Duex JE, Nau JJ, Kauffman EJ, Weisman LS . Apr 2006 . Phosphoinositide 5-phosphatase Fig 4p is required for both acute rise and subsequent fall in stress-induced phosphatidylinositol 3,5-bisphosphate levels . Eukaryotic Cell. 5 . 4. 723–31 . 16607019 . 10.1128/EC.5.4.723-731.2006 . 1459661 .