Alternative titles; symbols
HGNC Approved Gene Symbol: MYLIP
Cytogenetic location: 6p22.3 Genomic coordinates (GRCh38): 6:16,129,086-16,163,887 (from NCBI)
MYLIP belongs to the ezrin (VIL2; 123900)-radixin (RDX; 179410)-moesin (MSN; 309845) (ERM) family of cytoskeletal effector proteins that link actin to membrane-bound proteins at the cell surface (Olsson et al., 1999).
By database analysis and PCR of a fetal brain cDNA library, Olsson et al. (1999) cloned MYLIP, which they called MIR. The deduced 445-amino acid protein contains an N-terminal ERM homology domain and a C-terminal RING finger domain. Northern blot analysis detected a 3-kb MIR transcript in all human tissues examined, with prominent expression in placenta and fetal lung. Endogenous and fluorescence-tagged MIR showed a punctate, predominantly cytoplasmic distribution in COS-7 cells.
Using immunohistochemical analysis, Olsson et al. (2000) found that Mir was expressed in rat embryonic hippocampal neuronal cell bodies and growth cones. In rat PC12 neural precursor cells, Mir immunoreactivity was observed in neurites and in large-sized growth cones induced by Ngf (NGFB; 162030) treatment.
By yeast 2-hybrid analysis, Olsson et al. (1999) found that MIR interacted directly with myosin regulatory light chain B (MRLC2; 609211). Coimmunoprecipitation of cotransfected COS-7 cells confirmed the interaction. In rat PC12 cells, MIR overexpression inhibited NGF-induced neurite outgrowth, but it did not alter Trka (NTRK1; 191315) phosphorylation by NGF, suggesting MIR is downstream of TRKA.
Bornhauser et al. (2003) found that MIR and MSAP (TMEM4; 605861) interacted, but only if both proteins were full length. In rodent neuronal precursor cell lines, MIR reduced the stimulatory effect of MSAP overexpression on neurite outgrowth. MIR overexpression also resulted in ubiquitination of MRLC2, and this ubiquitination could be counteracted by MSAP overexpression.
Bornhauser et al. (2003) showed that the ERM domain of MIR increased the solubility of the full-length protein, whereas the RING domain was involved in protein-protein interactions and changes in cellular localization. The RING domain was responsible for the inhibitory activity of MIR on neurite outgrowth. Stability of the MIR protein was regulated by ubiquitination, including autoubiquitination, which was dependent upon cys387 within the RING domain.
Zelcer et al. (2009) demonstrated that the sterol-responsive nuclear liver X receptor (LXR) (see 600380) helps maintain cholesterol homeostasis, not only through promotion of cholesterol efflux but also through suppression of LDL uptake. LXR inhibits the LDLR (606945) pathway through the transcriptional induction of IDOL (MYLIP), an E3 ubiquitin ligase that triggers ubiquitination of the LDLR on its cytoplasmic domain, thereby targeting it for degradation. LXR ligand reduced, whereas LXR knockout increased, LDLR protein levels in vivo in a tissue-selective manner. IDOL knockdown in hepatocytes increased LDLR protein levels and promoted LDL uptake. Conversely, Zelcer et al. (2009) found that adenovirus-mediated expression of IDOL in mouse liver promoted LDLR degradation and elevated plasma LDL levels. Zelcer et al. (2009) concluded that the LXR-IDOL-LDLR axis defines a complementary pathway to sterol response element-binding proteins for sterol regulation of cholesterol uptake.
By genomic sequence analysis, Olsson et al. (2000) mapped the MYLIP gene to chromosome 6p23-p22.3.
Bornhauser, B. C., Johansson, C., Lindholm, D. Functional activities and cellular localization of the ezrin, radixin, moesin (ERM) and RING zinc finger domains in MIR. FEBS Lett. 553: 195-199, 2003. [PubMed: 14550572] [Full Text: https://doi.org/10.1016/s0014-5793(03)01010-x]
Bornhauser, B. C., Olsson, P.-A., Lindholm, D. MSAP is a novel MIR-interacting protein that enhances neurite outgrowth and increases myosin regulatory light chain. J. Biol. Chem. 278: 35412-35420, 2003. [PubMed: 12826659] [Full Text: https://doi.org/10.1074/jbc.M306271200]
Olsson, P.-A., Bornhauser, B. C., Korhonen, L., Lindholm, D. Neuronal expression of the ERM-like protein MIR in rat brain and its localization to human chromosome 6. Biochem. Biophys. Res. Commun. 279: 879-883, 2000. [PubMed: 11162443] [Full Text: https://doi.org/10.1006/bbrc.2000.4028]
Olsson, P.-A., Korhonen, L., Mercer, E. A., Lindholm, D. MIR is a novel ERM-like protein that interacts with myosin regulatory light chain and inhibits neurite outgrowth. J. Biol. Chem. 274: 36288-36292, 1999. [PubMed: 10593918] [Full Text: https://doi.org/10.1074/jbc.274.51.36288]
Zelcer, N., Hong, C., Boyadjian, R., Tontonoz, P. LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor. Science 325: 100-104, 2009. [PubMed: 19520913] [Full Text: https://doi.org/10.1126/science.1168974]