Novel mechanisms of MITF regulation identified in a mouse suppressor screen.

Autor:	Vu HN; Department of Biochemistry and Molecular Biology, BioMedical Center, Faculty of Medicine, University of Iceland, Sturlugata 8, 102, Reykjavík, Iceland., Valdimarsson MM; Department of Biochemistry, Science Institute, School of Engineering and Natural Sciences, University of Iceland, Sturlugata 7, 102, Reykjavík, Iceland., Sigurbjörnsdóttir S; Department of Biochemistry and Molecular Biology, BioMedical Center, Faculty of Medicine, University of Iceland, Sturlugata 8, 102, Reykjavík, Iceland., Bergsteinsdóttir K; Department of Biochemistry and Molecular Biology, BioMedical Center, Faculty of Medicine, University of Iceland, Sturlugata 8, 102, Reykjavík, Iceland., Debbache J; Mammalian Development Section, NINDS, NIH, Bethesda, MD, 20892-3706, USA., Bismuth K; Mammalian Development Section, NINDS, NIH, Bethesda, MD, 20892-3706, USA., Swing DA; Mouse Cancer Genetics Program, NCI, Frederick, MD, 21702-1201, USA., Hallsson JH; Department of Biochemistry and Molecular Biology, BioMedical Center, Faculty of Medicine, University of Iceland, Sturlugata 8, 102, Reykjavík, Iceland., Larue L; Institut Curie, PSL Research University, INSERM U1021, Normal and Pathological Development of Melanocytes, 91405, Orsay, France., Arnheiter H; Mammalian Development Section, NINDS, NIH, Bethesda, MD, 20892-3706, USA., Copeland NG; Mouse Cancer Genetics Program, NCI, Frederick, MD, 21702-1201, USA.; Genetics Department, MD Anderson Cancer Center, Houston, TX, 77030, USA., Jenkins NA; Mouse Cancer Genetics Program, NCI, Frederick, MD, 21702-1201, USA.; Genetics Department, MD Anderson Cancer Center, Houston, TX, 77030, USA., Heidarsson PO; Department of Biochemistry, Science Institute, School of Engineering and Natural Sciences, University of Iceland, Sturlugata 7, 102, Reykjavík, Iceland., Steingrímsson E; Department of Biochemistry and Molecular Biology, BioMedical Center, Faculty of Medicine, University of Iceland, Sturlugata 8, 102, Reykjavík, Iceland. eirikurs@hi.is.
Jazyk:	angličtina
Zdroj:	EMBO reports [EMBO Rep] 2024 Oct; Vol. 25 (10), pp. 4252-4280. Date of Electronic Publication: 2024 Aug 21.
DOI:	10.1038/s44319-024-00225-3
Abstrakt:	MITF, a basic Helix-Loop-Helix Zipper (bHLHZip) transcription factor, plays vital roles in melanocyte development and functions as an oncogene. We perform a genetic screen for suppressors of the Mitf-associated pigmentation phenotype in mice and identify an intragenic Mitf mutation that terminates MITF at the K316 SUMOylation site, leading to loss of the C-end intrinsically disordered region (IDR). The resulting protein is more nuclear but less stable than wild-type MITF and retains DNA-binding ability. As a dimer, it can translocate wild-type and mutant MITF partners into the nucleus, improving its own stability thus ensuring nuclear MITF supply. smFRET analysis shows interactions between K316 SUMOylation and S409 phosphorylation sites across monomers; these interactions largely explain the observed effects. The recurrent melanoma-associated E318K mutation in MITF, which affects K316 SUMOylation, also alters protein regulation in concert with S409. This suggests that residues K316 and S409 of MITF are impacted by SUMOylation and phosphorylation, respectively, mediating effects on nuclear localization and stability through conformational changes. Our work provides a novel mechanism of genetic suppression, and an example of how apparently deleterious mutations lead to normal phenotypes. (© 2024. The Author(s).)
Databáze:	MEDLINE
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