FIG4
Identifiers
AliasesFIG4, ALS11, CMT4J, KIAA0274, SAC3, YVS, dJ249I4.1, BTOP, Fig4, FIG4 phosphoinositide 5-phosphatase
External IDsOMIM: 609390 MGI: 2143585 HomoloGene: 6713 GeneCards: FIG4
Orthologs
SpeciesHumanMouse
Entrez

9896

103199

Ensembl

ENSG00000112367

ENSMUSG00000038417

UniProt

Q92562

Q91WF7

RefSeq (mRNA)

NM_014845

NM_133999

RefSeq (protein)

NP_055660

NP_598760

Location (UCSC)Chr 6: 109.69 – 109.88 MbChr 10: 41.06 – 41.18 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[5] Fig4 is an abbreviation for Factor-Induced Gene.[6]

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.[7] 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.[8] There are 5 human genes containing a Sac1 domain. Three of these genes (gene symbols SACM1L, INPP5F and FIG4), harbor a single Sac1 domain.[9] In the other two genes, synaptojanin 1 and 2, the Sac1 domain coexists with another phosphoinositide phosphatase domain, with both domains supporting phosphate hydrolysis.[10][11][12] In humans, the FIG4 gene localizes on chromosome 6 and encodes a Sac3 protein of 907 amino acids.[13] Sac3 is characterized as a widespread 97-kDa protein that, in in vitro assays, displays phosphatase activity towards a range of 5’-phosphorylated phosphoinositides.[14][15] 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.[16][17] 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.[16][17] 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,[18] perinatal,[19] or early juvenile lethality[20] 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.[16][21] The C-terminal part of Sac3 is essential for this interaction.[17] 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.[22]

Medical significance

Mutations in the FIG4 gene cause a rare autosomal recessive Charcot-Marie-Tooth peripheral neuropathy type 4J (CMT4J).[20] 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.[23] 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.[21] Consequently, the Sac3I41T protein level in patient fibroblasts is from very low to undetectable.[24][25] Clinically, the onset and severity of CMT4J symptoms vary markedly, suggesting an important role of genetic background in the individual course of disease.[25] In two siblings, with severe peripheral motor deficits and moderate sensory symptoms, the disease had relatively little impact on the central nervous system.[26] 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.[27] 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.[27] FIG4 mutations are also found (without proven causation) in patients with amyotrophic lateral sclerosis (ALS)[28] 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).[20][24] Neuronal autophagy has been suggested as an important consequence of the knockout,[29] however, its primary relevance is disputed.[30] The plt mice show distinct morphological defects in motor and central neurons on the one hand, and sensory neurons - on the other.[30] 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.[24]

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.[31] Yeast Fig4p is a specific PtdIns(3,5)P2 5’-phosphatase, which physically interacts with Vac14p (the ortholog of human ArPIKfyve),[32] and the PtdIns(3,5)P2-producing enzyme Fab1p (the ortholog of PIKfyve).[33] The yeast Fab1p-Vac14p-Fig4p complex also involves Vac7p and potentially Atg18p.[34] 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.[35] 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.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000112367 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000038417 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ "Entrez Gene: FIG4 FIG4 homolog, SAC1 lipid phosphatase domain containing (S. cerevisiae)".
  6. ↑ Erdman S, Lin L, Malczynski M, Snyder M (February 1998). "Pheromone-regulated genes required for yeast mating differentiation". Journal of Cell Biology. 140 (3): 461–83. doi:10.1083/jcb.140.3.461. PMC 2140177. PMID 9456310.
  7. ↑ Hughes WE, Cooke FT, Parker PJ (Sep 2000). "Sac phosphatase domain proteins". Biochemical Journal. 350 (2): 337–52. doi:10.1042/0264-6021:3500337. PMC 1221260. PMID 10947947.
  8. ↑ Novick P, Osmond BC, Botstein D (Apr 1989). "Suppressors of yeast actin mutations". Genetics. 121 (4): 659–74. doi:10.1093/genetics/121.4.659. PMC 1203651. PMID 2656401.
  9. ↑ 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. doi:10.1074/jbc.M101579200. PMID 11274189.
  10. ↑ Majerus PW, York JD (Apr 2009). "Phosphoinositide phosphatases and disease". Journal of Lipid Research. 50 (Suppl): S249–54. doi:10.1194/jlr.R800072-JLR200. PMC 2674710. PMID 19001665.
  11. ↑ 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. doi:10.1016/j.plipres.2009.06.001. PMID 19580826.
  12. ↑ Liu Y, Bankaitis VA (Jul 2010). "Phosphoinositide phosphatases in cell biology and disease". Progress in Lipid Research. 49 (3): 201–17. doi:10.1016/j.plipres.2009.12.001. PMC 2873057. PMID 20043944.
  13. ↑ 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. doi:10.1093/dnares/3.5.321. PMID 9039502.
  14. ↑ 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. doi:10.1074/jbc.M611678200. PMID 17556371.
  15. ↑ 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. doi:10.1038/cr.2007.82. PMID 17909536.
  16. 1 2 3 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. doi:10.1016/j.jmb.2008.10.009. PMC 2756758. PMID 18950639.
  17. 1 2 3 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. doi:10.1074/jbc.M109.037515. PMC 2791009. PMID 19840946.
  18. ↑ 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. doi:10.1074/jbc.M111.222364. PMC 3075686. PMID 21349843.
  19. ↑ 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. Bibcode:2007PNAS..10417518Z. doi:10.1073/pnas.0702275104. PMC 2077288. PMID 17956977.
  20. 1 2 3 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. Bibcode:2007Natur.448...68C. doi:10.1038/nature05876. PMC 2271033. PMID 17572665.
  21. 1 2 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. doi:10.1074/jbc.C110.154658. PMC 2930674. PMID 20630877.
  22. ↑ 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. doi:10.1074/jbc.M109.025361. PMC 2781990. PMID 19578118.
  23. ↑ 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. doi:10.1093/brain/awr148. PMC 3122378. PMID 21705420.
  24. 1 2 3 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. doi:10.1371/journal.pgen.1002104. PMC 3107197. PMID 21655088.
  25. 1 2 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. doi:10.1002/ana.25198. PMC 5912982. PMID 29518270.
  26. ↑ 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. doi:10.1093/brain/awn114. PMC 2724900. PMID 18556664.
  27. 1 2 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. doi:10.1007/s12035-019-01693-8. PMID 31313076. S2CID 197423698.
  28. ↑ 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. doi:10.1016/j.ajhg.2008.12.010. PMC 2668033. PMID 19118816.
  29. ↑ 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. doi:10.1093/hmg/ddp460. PMC 2778378. PMID 19793721.
  30. 1 2 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. doi:10.1111/j.1460-9568.2011.07651.x. PMID 21410794. S2CID 24916509.
  31. ↑ 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. doi:10.1083/jcb.140.3.461. PMC 2140177. PMID 9456310.
  32. ↑ 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. doi:10.1091/mbc.E03-05-0297. PMC 307524. PMID 14528018.
  33. ↑ 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. doi:10.1091/mbc.E08-04-0405. PMC 2555960. PMID 18653468.
  34. ↑ 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. doi:10.1038/emboj.2008.248. PMC 2600653. PMID 19037259.
  35. ↑ 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. doi:10.1128/EC.5.4.723-731.2006. PMC 1459661. PMID 16607019.

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