Phosphatase Subfamily FIG4

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Phosphatase Classification: Fold CC1: Superfamily CC1: Family Sac: Subfamily FIG4 (SAC3)

FIG4 (SAC3) is a phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) phosphatase located in the vacuolar membrane. It is associated with a form of Charcot-Marie-Tooth disorder CMT4J, Yunis-Varón syndrome, and amyotrophic lateral sclerosis (ALS). FIG4 is found in most if not all eukaryotes.


The FIG4 is found in almost all eukaryotes, including a single gene in human (FIG4/SAC3).


FIG4 has a single structural domain, SAC phosphatase domain.


FIG4 (SAC3) is a phosphatase specificity for 5'-phosphate of phosphatidylinositol-3,5-diphosphate (PI3,5P2; PtdIns(3,5)P2), a rare phosphoinositide (<1% of total PI in mammalian cells) that mediates essential aspects of endocytic membrane homeostasis and coordinates fission and fusion events in the multivesicular endosomal system of mammalian cells [1]. PtdIns(3,5)P2 is found in the vacuolar membrane, and levels are regulated by FIG4, PIKfyve (the sole kinase for PtdIns(3,5)P2 synthesis) and the PIKfyve activator ArPIKfyve [2]. The triple PIKfyve-ArPIKfyve-Sac3 (PAS) complex ensures the PtdIns(3,5)P2 homeostatic control by rapid turnover counterbalancing locally elevated PtdIns(3,5)P2 [1]. A model of domain interactions within the PAS core and their role in regulating the enzymatic activities was summarized in Figure 6 of [1].

Mutations in FIG4 cause neurodegeneration in patients with a form of autosomal recessive Charcot-Marie-Tooth disorder, CMT4J and in the pale tremor mouse [3, 4, 5]. It also causes Yunis-Varón syndrome [6, 7]. In addition, it is also a risk factor of amyotrophic lateral sclerosis (ALS) [8, 9].

FIG4 is widely expressed in different tissues (see GTEx).,


  1. Ikonomov OC, Sbrissa D, Fenner H, and Shisheva A. PIKfyve-ArPIKfyve-Sac3 core complex: contact sites and their consequence for Sac3 phosphatase activity and endocytic membrane homeostasis. J Biol Chem. 2009 Dec 18;284(51):35794-806. DOI:10.1074/jbc.M109.037515 | PubMed ID:19840946 | HubMed [Ikonomov09]
  2. Zou J, Hu B, Arpag S, Yan Q, Hamilton A, Zeng YS, Vanoye CG, and Li J. Reactivation of Lysosomal Ca2+ Efflux Rescues Abnormal Lysosomal Storage in FIG4-Deficient Cells. J Neurosci. 2015 Apr 29;35(17):6801-12. DOI:10.1523/JNEUROSCI.4442-14.2015 | PubMed ID:25926456 | HubMed [Zou15]
  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, and Meisler MH. Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J. Nature. 2007 Jul 5;448(7149):68-72. DOI:10.1038/nature05876 | PubMed ID:17572665 | HubMed [Chow07]
  4. Ikonomov OC, Sbrissa D, Fligger J, Delvecchio K, and Shisheva A. ArPIKfyve regulates Sac3 protein abundance and turnover: disruption of the mechanism by Sac3I41T mutation causing Charcot-Marie-Tooth 4J disorder. J Biol Chem. 2010 Aug 27;285(35):26760-4. DOI:10.1074/jbc.C110.154658 | PubMed ID:20630877 | HubMed [Ikonomov10]
  5. 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, and Meisler MH. Distinctive genetic and clinical features of CMT4J: a severe neuropathy caused by mutations in the PI(3,5)P₂ phosphatase FIG4. Brain. 2011 Jul;134(Pt 7):1959-71. DOI:10.1093/brain/awr148 | PubMed ID:21705420 | HubMed [Nicholson11]
  6. Campeau PM, Lenk GM, Lu JT, Bae Y, Burrage L, Turnpenny P, Román Corona-Rivera J, Morandi L, Mora M, Reutter H, Vulto-van Silfhout AT, Faivre L, Haan E, Gibbs RA, Meisler MH, and Lee BH. Yunis-Varón syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase. Am J Hum Genet. 2013 May 2;92(5):781-91. DOI:10.1016/j.ajhg.2013.03.020 | PubMed ID:23623387 | HubMed [Campeau13]
  7. Nakajima J, Okamoto N, Shiraishi J, Nishimura G, Nakashima M, Tsurusaki Y, Saitsu H, Kawashima H, Matsumoto N, and Miyake N. Novel FIG4 mutations in Yunis-Varon syndrome. J Hum Genet. 2013 Dec;58(12):822-4. DOI:10.1038/jhg.2013.104 | PubMed ID:24088667 | HubMed [Nakajima13]
  8. 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, and Meisler MH. Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS. Am J Hum Genet. 2009 Jan;84(1):85-8. DOI:10.1016/j.ajhg.2008.12.010 | PubMed ID:19118816 | HubMed [Chow09]
  9. Kon T, Mori F, Tanji K, Miki Y, Toyoshima Y, Yoshida M, Sasaki H, Kakita A, Takahashi H, and Wakabayashi K. ALS-associated protein FIG4 is localized in Pick and Lewy bodies, and also neuronal nuclear inclusions, in polyglutamine and intranuclear inclusion body diseases. Neuropathology. 2014 Feb;34(1):19-26. DOI:10.1111/neup.12056 | PubMed ID:23888880 | HubMed [Kon14]
  10. Sbrissa D, Ikonomov OC, Fu Z, Ijuin T, Gruenberg J, Takenawa T, and Shisheva A. 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. J Biol Chem. 2007 Aug 17;282(33):23878-91. DOI:10.1074/jbc.M611678200 | PubMed ID:17556371 | HubMed [Sbrissa07]
  11. Sbrissa D, Ikonomov OC, Fenner H, and Shisheva A. ArPIKfyve homomeric and heteromeric interactions scaffold PIKfyve and Sac3 in a complex to promote PIKfyve activity and functionality. J Mol Biol. 2008 Dec 26;384(4):766-79. DOI:10.1016/j.jmb.2008.10.009 | PubMed ID:18950639 | HubMed [Sbrissa08]
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