FBXL2
F-box/LRR-repeat protein 2 is a protein that in humans is encoded by the FBXL2 gene.[4][5][6]
This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class and, in addition to an F-box, contains 12 tandem leucine-rich repeats.[6]
FBXL2 is a highly conserved F-box protein that directly binds substrates and, thus, determines the specificity of the SCF ubiquitin ligase complex. FBXL2 contains a typical CaaX motif that is post-translationally modified by geranyl-geranylation for targeting to cellular membranes.[7][8][9] The importance of the ubiquitin ligase activity of FBXL2 was originally shown in an unbiased screen for cellular host factors necessary for Hepatitis C virus (HCV) replication.[7] Geranyl-geranylation of FBXL2 is essential also for its pro-survival function in mediating poly-ubiquitylation and proteasomal degradation of IP3R3 (a calcium channel at the endoplasmic reticulum)[9] and p85β (the regulatory subunit of PI3-Kinases).[8]
PI3Ks are heterodimeric lipid kinases composed of a p110 catalytic subunit and a p85 regulatory subunit. FBXL2 interacts with the pool of p85β that is free of p110 subunits to promote p85β, but not p85α, degradation.[8] The degradation of p85β via FBXL2 maintains the balance between p85β monomers and p110-p85 heterodimers for efficient activation of PI3K in response to mitogens.
In response to IP3 (inositol 1,4,5-trisphosphate) production, calcium (Ca2+) flux between the endoplasmic reticulum (ER) and mitochondria is carried out by IP3 receptors (IP3Rs). This event is critical for cellular bioenergetics. The duration and the extent of Ca2+ release from IP3Rs determine whether cells survive or die: basal levels of Ca2+ release and uptake by the mitochondria is necessary for oxidative phosphorylation and ATP production. However, excessive and/or persistent Ca2+ flux results in mitochondrial Ca2+ overload and apoptosis. FBXL2 targets IP3R3 for degradation to avoid an excessive and prolonged flux of Ca2+ and to attenuate apoptosis in response to stress.[9] This process requires presence of FBXL2 at membranes via geranyl-geranylation, and is sensitive to GGTi-2418 (a CaaX peptidomimetic geranyl-geranylation inhibitor that reached clinical trials). The degradation of IP3R3 is antagonized by the tumor suppressor PTEN, which competes with FBXL2 for binding to IP3R3, thereby preventing IP3R3 degradation and promoting cell death.
References
- 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000032507 - Ensembl, May 2017
- ↑ "Human PubMed Reference:".
- ↑ "Mouse PubMed Reference:".
- ↑ Ilyin GP, Rialland M, Glaise D, Guguen-Guillouzo C (Nov 1999). "Identification of a novel Skp2-like mammalian protein containing F-box and leucine-rich repeats". FEBS Lett. 459 (1): 75–9. doi:10.1016/S0014-5793(99)01211-9. PMID 10508920.
- ↑ Cenciarelli C, Chiaur DS, Guardavaccaro D, Parks W, Vidal M, Pagano M (Dec 1999). "Identification of a family of human F-box proteins". Curr Biol. 9 (20): 1177–9. doi:10.1016/S0960-9822(00)80020-2. PMID 10531035.
- 1 2 "Entrez Gene: FBXL2 F-box and leucine-rich repeat protein 2".
- 1 2 Wang, C. et al. Identification of FBL2 as a geranylgeranylated cellular protein required for hepatitis C virus RNA replication. Mol Cell 18, 425-434 (2005).
- 1 2 3 Kuchay, S. et al. FBXL2- and PTPL1-mediated degradation of p110-free p85beta regulatory subunit controls the PI(3)K signalling cascade. Nat Cell Biol 15, 472-480, doi:10.1038/ncb2731 (2013).
- 1 2 3 Kuchay, S. et al. PTEN counteracts FBXL2 to promote IP3R3- and Ca(2+)-mediated apoptosis limiting tumour growth. Nature 546, 554-558, doi:10.1038/nature22965 (2017).
Further reading
- Ye J (2007). "Reliance of Host Cholesterol Metabolic Pathways for the Life Cycle of Hepatitis C Virus". PLoS Pathog. 3 (8): e108. doi:10.1371/journal.ppat.0030108. PMC 1959368. PMID 17784784.
- Winston JT, Koepp DM, Zhu C, et al. (1999). "A family of mammalian F-box proteins". Curr. Biol. 9 (20): 1180–2. doi:10.1016/S0960-9822(00)80021-4. PMID 10531037.
- Ilyin GP, Rialland M, Pigeon C, Guguen-Guillouzo C (2001). "cDNA cloning and expression analysis of new members of the mammalian F-box protein family". Genomics. 67 (1): 40–7. doi:10.1006/geno.2000.6211. PMID 10945468.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
- Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The Status, Quality, and Expansion of the NIH Full-Length cDNA Project: The Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
- Wang C, Gale M, Keller BC, et al. (2005). "Identification of FBL2 as a geranylgeranylated cellular protein required for hepatitis C virus RNA replication". Mol. Cell. 18 (4): 425–34. doi:10.1016/j.molcel.2005.04.004. PMID 15893726.
- Rual JF, Venkatesan K, Hao T, et al. (2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. doi:10.1038/nature04209. PMID 16189514.