Alternative titles; symbols
HGNC Approved Gene Symbol: MIOS
Cytogenetic location: 7p21.3 Genomic coordinates (GRCh38): 7:7,566,884-7,609,144 (from NCBI)
In Drosophila, Mio is required for oocyte development (Iida and Lilly, 2004).
Iida and Lilly (2004) cloned Drosophila Mio, and by database analysis, they identified orthologs conserved from yeast to humans. The deduced 867-amino acid fly protein shares 30% identity with human MIOS. Mio orthologs have an N-terminal WD40 repeat region and a C-terminal zinc finger-like domain. In mammals, the WD40 repeat domain contains 6 WD40 repeats and in flies, only 4. Immunohistochemical analysis revealed that Mio was expressed in fly pro-oocyte nuclei in early prophase of meiosis I.
Hartz (2013) mapped the MIOS gene to chromosome 7p21.3 based on an alignment of the MIOS sequence (GenBank AK000330) with the genomic sequence (GRCh37).
Bar-Peled et al. (2013) identified the octameric GATOR (GTPase-activating protein (GAP) activity toward RAGs) complex as a critical regulator of the pathway that signals amino acid sufficiency to mTORC1 (see 601231). GATOR is composed of 2 subcomplexes, GATOR1 and GATOR2. Inhibition of the GATOR1 subunits DEPDC5 (614191), NPRL2 (607072), and NPRL3 (600928) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of the GATOR2 subunits MIOS, WDR24 (620307), WDR59 (617418), SEH1L (609263), and SEC13 (600152) suppresses mTORC1 signaling, and epistasis analysis shows that GATOR2 negatively regulates DEPDC5. GATOR1 has GAP activity for RAGA (612194) and RAGB (300725), and its components are mutated in human cancer. In cancer cells with inactivating mutations in GATOR1, mTORC1 is hyperactive and insensitive to amino acid starvation, and such cells are hypersensitive to rapamycin, an mTORC1 inhibitor. Thus, Bar-Peled et al. (2013) concluded that they had identified a key negative regulator of the RAG GTPases and revealed that, like other mTORC1 regulators, RAG function can be deregulated in cancer.
Using cryoelectron microscopy, Valenstein et al. (2022) determined the structure of the human GATOR2 complex at an overall resolution of 3.7 angstroms. GATOR2 adopted a 2-fold rotationally symmetric, cage-like architecture built from 2 WDR24-SEH1L, 4 MIOS-SEH1L, and 2 WDR59-SEC13 heterodimers that assembled together to form an octagonal scaffold with protruding pairs of WD40 beta propellers. The core subunits, WDR24, MIOS, and WDR59, each have a C-terminal domain (CTD) composed of a zinc finger and a RING domain, and they shared a similar fold. Consistent with their key roles in GATOR2 assembly, WDR24, MIOS, and WDR59 were each required for mTORC1 to sense amino acid availability. The 6-bladed beta-propeller proteins SEH1L and SEC13 were incorporated into the GATOR2 scaffold through a beta-blade donation by WDR24 or MIOS and WDR59, respectively. The surface of GATOR2 was highly charged with interspersed lipophilic patches. GATOR2 contained a total of 8 beta-propeller pairs, including 4 central pairs composed of MIOS and SEH1L beta-propeller dimers. MIOS interacted with WDR24 and WDR59 to form heterodimers through their CTDs: 2 between the C termini of MIOS and WDR24, and 2 between the CTDs of MIOS and WDR59, thereby linking 4 MIOS to 2 WDR24 and 2 WDR59. Despite the presence of multiple RING domains, the GATOR2 structure suggested that it does not possess E3 ubiquitin ligase activity, which was confirmed by subsequent biochemical analysis. The alpha-solenoid junctions of SEH1L and SEC13 circularized the GATOR2 complex to complete the scaffold. The GATOR2 complex used beta propellers to engage with amino acid sensors and GATOR1 to regulate mTORC1. Specifically, the MIOS and WDR24 beta propellers received inputs from cytosolic amino acid sensors, and the WDR24 and WDR59 propellers transduced amino acid availability to mTORC1.
In Drosophila, a single oocyte and 15 polyploid nurse cells develop within a 16-cell germline cyst. Iida and Lilly (2004) found that 2 Drosophila strains with null mutations in the Mio gene were viable, but female sterile. All cells of the female germline cyst were polyploid. Mio was not required for oocyte specificity or for progression to pachytene, but was required at later stages of oogenesis for meiotic progression and maintenance of oocyte cell fate. Inhibition of double-strand breaks during meiosis significantly suppressed the 16-nurse cell phenotype and associated developmental delay.
Bar-Peled, L., Chantranupong, L., Cherniack, A. D., Chen, W. W., Ottina, K. A., Grabiner, B. C., Spear, E. D., Carter, S. L., Meyerson, M., Sabatini, D. M. A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science 340: 1100-1106, 2013. [PubMed: 23723238] [Full Text: https://doi.org/10.1126/science.1232044]
Hartz, P. A. Personal Communication. Baltimore, Md. 8/5/2013.
Iida, T., Lilly, M. A. Missing oocyte encodes a highly conserved nuclear protein required for the maintenance of the meiotic cycle and oocyte identity in Drosophila. Development 131: 1029-1031, 2004. [PubMed: 14973288] [Full Text: https://doi.org/10.1242/dev.01001]
Valenstein, M. L., Rogala, K. B., Lalgudi, P. V., Brignole, E. J., Gu, X., Saxton, R. A., Chantranupong, L., Kolibius, J., Quast, J.-P., Sabatini, D. M. Structure of the nutrient-sensing hub GATOR2. Nature 607: 610-616, 2022. [PubMed: 35831510] [Full Text: https://doi.org/10.1038/s41586-022-04939-z]