Subcellular localization and stability of MITF are modulated by the bHLH-Zip domain

Valerie Fock; Sigurdur Runar Gudmundsson; Hilmar Orn Gunnlaugsson; Jon August Stefansson; Vivien Ionasz; Alexander Schepsky; Jade Viarigi; Indridi Einar Reynisson; Vivian Pogenberg; Matthias Wilmanns; Margret Helga Ogmundsdottir; Eirikur Steingrimsson

doi:10.1111/pcmr.12721

Subcellular localization and stability of MITF are modulated by the bHLH-Zip domain

Valerie Fock
, Sigurdur Runar Gudmundsson
, Hilmar Orn Gunnlaugsson
, Jon August Stefansson
, Vivien Ionasz
, Alexander Schepsky
, Jade Viarigi
, Indridi Einar Reynisson
, Vivian Pogenberg
, Matthias Wilmanns
, Margret Helga Ogmundsdottir
, Eirikur Steingrimsson

University of Iceland

Research output: Contribution to journal › Article › peer-review

Abstract

Microphthalmia-associated transcription factor (MITF) is a member of the basic helix–loop–helix leucine zipper (bHLH-Zip) family and functions as the master regulator of the melanocytic lineage. MITF-M is the predominant isoform expressed in melanocytes and melanoma cells, and, unlike other MITF isoforms, it is constitutively nuclear. Mutational analysis revealed three karyophilic signals in the bHLH-Zip domain of MITF-M, spanning residues 197–206, 214–217, and 255–265. Structural characterization of the MITF protein showed that basic residues within these signals are exposed for interactions in the absence of DNA. Moreover, our data indicate that neither DNA binding nor dimerization of MITF-M are required for its nuclear localization. Finally, dimerization-deficient MITF-M mutants exhibited a significantly reduced stability in melanoma cells when compared to the wild-type protein. Taken together, we have shown that, in addition to its well-established role in DNA binding and dimer formation, the bHLH-Zip domain of MITF modulates the transcription factor's subcellular localization and stability.

Original language	English
Pages (from-to)	41-54
Number of pages	14
Journal	Pigment Cell and Melanoma Research
Volume	32
Issue number	1
DOIs	https://doi.org/10.1111/pcmr.12721
Publication status	Published - Jan 2019

Bibliographical note

Funding Information: and 130230-052 from the Research Fund of Iceland (E.S.) and by an Erwin Schrödinger fellowship (J 3864-B26) from the Austrian Science Fund (V.F.). The authors declare no competing financial interests. Publisher Copyright: © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Other keywords

MITF
Waardenburg syndrome
bHLH-Zip
nuclear localization
stability

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1111/pcmr.12721

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Fock, V., Gudmundsson, S. R., Gunnlaugsson, H. O., Stefansson, J. A., Ionasz, V., Schepsky, A., Viarigi, J., Reynisson, I. E., Pogenberg, V., Wilmanns, M., Ogmundsdottir, M. H., & Steingrimsson, E. (2019). Subcellular localization and stability of MITF are modulated by the bHLH-Zip domain. Pigment Cell and Melanoma Research, 32(1), 41-54. https://doi.org/10.1111/pcmr.12721

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title = "Subcellular localization and stability of MITF are modulated by the bHLH-Zip domain",

abstract = "Microphthalmia-associated transcription factor (MITF) is a member of the basic helix–loop–helix leucine zipper (bHLH-Zip) family and functions as the master regulator of the melanocytic lineage. MITF-M is the predominant isoform expressed in melanocytes and melanoma cells, and, unlike other MITF isoforms, it is constitutively nuclear. Mutational analysis revealed three karyophilic signals in the bHLH-Zip domain of MITF-M, spanning residues 197–206, 214–217, and 255–265. Structural characterization of the MITF protein showed that basic residues within these signals are exposed for interactions in the absence of DNA. Moreover, our data indicate that neither DNA binding nor dimerization of MITF-M are required for its nuclear localization. Finally, dimerization-deficient MITF-M mutants exhibited a significantly reduced stability in melanoma cells when compared to the wild-type protein. Taken together, we have shown that, in addition to its well-established role in DNA binding and dimer formation, the bHLH-Zip domain of MITF modulates the transcription factor's subcellular localization and stability.",

keywords = "MITF, Waardenburg syndrome, bHLH-Zip, nuclear localization, stability",

author = "Valerie Fock and Gudmundsson, \{Sigurdur Runar\} and Gunnlaugsson, \{Hilmar Orn\} and Stefansson, \{Jon August\} and Vivien Ionasz and Alexander Schepsky and Jade Viarigi and Reynisson, \{Indridi Einar\} and Vivian Pogenberg and Matthias Wilmanns and Ogmundsdottir, \{Margret Helga\} and Eirikur Steingrimsson",

note = "Funding Information: and 130230-052 from the Research Fund of Iceland (E.S.) and by an Erwin Schr{\"o}dinger fellowship (J 3864-B26) from the Austrian Science Fund (V.F.). The authors declare no competing financial interests. Publisher Copyright: {\textcopyright} 2018 John Wiley \& Sons A/S. Published by John Wiley \& Sons Ltd",

year = "2019",

month = jan,

doi = "10.1111/pcmr.12721",

language = "English",

volume = "32",

pages = "41--54",

journal = "Pigment Cell and Melanoma Research",

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T1 - Subcellular localization and stability of MITF are modulated by the bHLH-Zip domain

AU - Fock, Valerie

AU - Gudmundsson, Sigurdur Runar

AU - Gunnlaugsson, Hilmar Orn

AU - Stefansson, Jon August

AU - Ionasz, Vivien

AU - Schepsky, Alexander

AU - Viarigi, Jade

AU - Reynisson, Indridi Einar

AU - Pogenberg, Vivian

AU - Wilmanns, Matthias

AU - Ogmundsdottir, Margret Helga

AU - Steingrimsson, Eirikur

N1 - Funding Information: and 130230-052 from the Research Fund of Iceland (E.S.) and by an Erwin Schrödinger fellowship (J 3864-B26) from the Austrian Science Fund (V.F.). The authors declare no competing financial interests. Publisher Copyright: © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

PY - 2019/1

Y1 - 2019/1

N2 - Microphthalmia-associated transcription factor (MITF) is a member of the basic helix–loop–helix leucine zipper (bHLH-Zip) family and functions as the master regulator of the melanocytic lineage. MITF-M is the predominant isoform expressed in melanocytes and melanoma cells, and, unlike other MITF isoforms, it is constitutively nuclear. Mutational analysis revealed three karyophilic signals in the bHLH-Zip domain of MITF-M, spanning residues 197–206, 214–217, and 255–265. Structural characterization of the MITF protein showed that basic residues within these signals are exposed for interactions in the absence of DNA. Moreover, our data indicate that neither DNA binding nor dimerization of MITF-M are required for its nuclear localization. Finally, dimerization-deficient MITF-M mutants exhibited a significantly reduced stability in melanoma cells when compared to the wild-type protein. Taken together, we have shown that, in addition to its well-established role in DNA binding and dimer formation, the bHLH-Zip domain of MITF modulates the transcription factor's subcellular localization and stability.

AB - Microphthalmia-associated transcription factor (MITF) is a member of the basic helix–loop–helix leucine zipper (bHLH-Zip) family and functions as the master regulator of the melanocytic lineage. MITF-M is the predominant isoform expressed in melanocytes and melanoma cells, and, unlike other MITF isoforms, it is constitutively nuclear. Mutational analysis revealed three karyophilic signals in the bHLH-Zip domain of MITF-M, spanning residues 197–206, 214–217, and 255–265. Structural characterization of the MITF protein showed that basic residues within these signals are exposed for interactions in the absence of DNA. Moreover, our data indicate that neither DNA binding nor dimerization of MITF-M are required for its nuclear localization. Finally, dimerization-deficient MITF-M mutants exhibited a significantly reduced stability in melanoma cells when compared to the wild-type protein. Taken together, we have shown that, in addition to its well-established role in DNA binding and dimer formation, the bHLH-Zip domain of MITF modulates the transcription factor's subcellular localization and stability.

KW - MITF

KW - Waardenburg syndrome

KW - bHLH-Zip

KW - nuclear localization

KW - stability

UR - https://www.scopus.com/pages/publications/85050375083

U2 - 10.1111/pcmr.12721

DO - 10.1111/pcmr.12721

M3 - Article

C2 - 29938923

SN - 1755-1471

VL - 32

SP - 41

EP - 54

JO - Pigment Cell and Melanoma Research

JF - Pigment Cell and Melanoma Research

IS - 1

ER -

Subcellular localization and stability of MITF are modulated by the bHLH-Zip domain

Abstract

Bibliographical note

Other keywords

UN SDGs

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