An atypical GABARAP binding module drives the pro-autophagic potential of the AML-associated NPM1c variant
Summary: The nucleolar scaffold protein NPM1 is a multifunctional regulator of cellular homeostasis, genome integrity, and stress response. NPM1 mutations, known as NPM1c variants promoting its aberrant cytoplasmic localization, are the most frequent genetic alterations in acute myeloid leukemia (AM...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723014961 |
| _version_ | 1797449519134146560 |
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| author | Hannah Mende Anshu Khatri Carolin Lange Sergio Alejandro Poveda-Cuevas Georg Tascher Adriana Covarrubias-Pinto Frank Löhr Sebastian E. Koschade Ivan Dikic Christian Münch Anja Bremm Lorenzo Brunetti Christian H. Brandts Hannah Uckelmann Volker Dötsch Vladimir V. Rogov Ramachandra M. Bhaskara Stefan Müller |
| author_facet | Hannah Mende Anshu Khatri Carolin Lange Sergio Alejandro Poveda-Cuevas Georg Tascher Adriana Covarrubias-Pinto Frank Löhr Sebastian E. Koschade Ivan Dikic Christian Münch Anja Bremm Lorenzo Brunetti Christian H. Brandts Hannah Uckelmann Volker Dötsch Vladimir V. Rogov Ramachandra M. Bhaskara Stefan Müller |
| author_sort | Hannah Mende |
| collection | DOAJ |
| description | Summary: The nucleolar scaffold protein NPM1 is a multifunctional regulator of cellular homeostasis, genome integrity, and stress response. NPM1 mutations, known as NPM1c variants promoting its aberrant cytoplasmic localization, are the most frequent genetic alterations in acute myeloid leukemia (AML). A hallmark of AML cells is their dependency on elevated autophagic flux. Here, we show that NPM1 and NPM1c induce the autophagy-lysosome pathway by activating the master transcription factor TFEB, thereby coordinating the expression of lysosomal proteins and autophagy regulators. Importantly, both NPM1 and NPM1c bind to autophagy modifiers of the GABARAP subfamily through an atypical binding module preserved within its N terminus. The propensity of NPM1c to induce autophagy depends on this module, likely indicating that NPM1c exerts its pro-autophagic activity by direct engagement with GABARAPL1. Our data report a non-canonical binding mode of GABARAP family members that drives the pro-autophagic potential of NPM1c, potentially enabling therapeutic options. |
| first_indexed | 2024-03-09T14:26:07Z |
| format | Article |
| id | doaj.art-c6187d86919640fc8c826a912248ef14 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-09T14:26:07Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-c6187d86919640fc8c826a912248ef142023-11-28T07:25:49ZengElsevierCell Reports2211-12472023-12-014212113484An atypical GABARAP binding module drives the pro-autophagic potential of the AML-associated NPM1c variantHannah Mende0Anshu Khatri1Carolin Lange2Sergio Alejandro Poveda-Cuevas3Georg Tascher4Adriana Covarrubias-Pinto5Frank Löhr6Sebastian E. Koschade7Ivan Dikic8Christian Münch9Anja Bremm10Lorenzo Brunetti11Christian H. Brandts12Hannah Uckelmann13Volker Dötsch14Vladimir V. Rogov15Ramachandra M. Bhaskara16Stefan Müller17Goethe University Frankfurt, Institute of Biochemistry II, Theodor-Stern-Kai 7, 60590 Frankfurt, GermanyGoethe University Frankfurt, Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Max-von-Laue Street 9, 60438 Frankfurt, GermanyGoethe University Frankfurt, Institute of Biochemistry II, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; Goethe University Frankfurt, Buchmann Institute for Molecular Life Sciences, Max-von-Laue Street 15, 60438 Frankfurt, GermanyGoethe University Frankfurt, Institute of Biochemistry II, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; Goethe University Frankfurt, Buchmann Institute for Molecular Life Sciences, Max-von-Laue Street 15, 60438 Frankfurt, GermanyGoethe University Frankfurt, Institute of Biochemistry II, Theodor-Stern-Kai 7, 60590 Frankfurt, GermanyGoethe University Frankfurt, Institute of Biochemistry II, Theodor-Stern-Kai 7, 60590 Frankfurt, GermanyGoethe University Frankfurt, Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Max-von-Laue Street 9, 60438 Frankfurt, GermanyGoethe University Frankfurt, Institute of Biochemistry II, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; Goethe University Frankfurt, University Hospital, Department of Medicine, Hematology/Oncology, Theodor-Stern-Kai 7, 60590 Frankfurt, GermanyGoethe University Frankfurt, Institute of Biochemistry II, Theodor-Stern-Kai 7, 60590 Frankfurt, GermanyGoethe University Frankfurt, Institute of Biochemistry II, Theodor-Stern-Kai 7, 60590 Frankfurt, GermanyGoethe University Frankfurt, Institute of Biochemistry II, Theodor-Stern-Kai 7, 60590 Frankfurt, GermanyMarche Polytechnic University, Department of Clinical and Molecular Sciences, Via Tronto 10, 60020 Ancona, ItalyGoethe University Frankfurt, University Hospital, Department of Medicine, Hematology/Oncology, Theodor-Stern-Kai 7, 60590 Frankfurt, GermanyGoethe University Frankfurt, University Hospital, Department of Pediatrics, Theodor-Stern-Kai 7, 60590 Frankfurt, GermanyGoethe University Frankfurt, Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Max-von-Laue Street 9, 60438 Frankfurt, GermanyGoethe University Frankfurt, Institute of Pharmaceutical Chemistry, Max-von-Laue Street 15, 60438 Frankfurt, Germany; Goethe University Frankfurt, Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Max-von-Laue Street 15, 60438 Frankfurt, GermanyGoethe University Frankfurt, Institute of Biochemistry II, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; Goethe University Frankfurt, Buchmann Institute for Molecular Life Sciences, Max-von-Laue Street 15, 60438 Frankfurt, Germany; Corresponding authorGoethe University Frankfurt, Institute of Biochemistry II, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; Corresponding authorSummary: The nucleolar scaffold protein NPM1 is a multifunctional regulator of cellular homeostasis, genome integrity, and stress response. NPM1 mutations, known as NPM1c variants promoting its aberrant cytoplasmic localization, are the most frequent genetic alterations in acute myeloid leukemia (AML). A hallmark of AML cells is their dependency on elevated autophagic flux. Here, we show that NPM1 and NPM1c induce the autophagy-lysosome pathway by activating the master transcription factor TFEB, thereby coordinating the expression of lysosomal proteins and autophagy regulators. Importantly, both NPM1 and NPM1c bind to autophagy modifiers of the GABARAP subfamily through an atypical binding module preserved within its N terminus. The propensity of NPM1c to induce autophagy depends on this module, likely indicating that NPM1c exerts its pro-autophagic activity by direct engagement with GABARAPL1. Our data report a non-canonical binding mode of GABARAP family members that drives the pro-autophagic potential of NPM1c, potentially enabling therapeutic options.http://www.sciencedirect.com/science/article/pii/S2211124723014961CP: CancerCP: Molecular biology |
| spellingShingle | Hannah Mende Anshu Khatri Carolin Lange Sergio Alejandro Poveda-Cuevas Georg Tascher Adriana Covarrubias-Pinto Frank Löhr Sebastian E. Koschade Ivan Dikic Christian Münch Anja Bremm Lorenzo Brunetti Christian H. Brandts Hannah Uckelmann Volker Dötsch Vladimir V. Rogov Ramachandra M. Bhaskara Stefan Müller An atypical GABARAP binding module drives the pro-autophagic potential of the AML-associated NPM1c variant Cell Reports CP: Cancer CP: Molecular biology |
| title | An atypical GABARAP binding module drives the pro-autophagic potential of the AML-associated NPM1c variant |
| title_full | An atypical GABARAP binding module drives the pro-autophagic potential of the AML-associated NPM1c variant |
| title_fullStr | An atypical GABARAP binding module drives the pro-autophagic potential of the AML-associated NPM1c variant |
| title_full_unstemmed | An atypical GABARAP binding module drives the pro-autophagic potential of the AML-associated NPM1c variant |
| title_short | An atypical GABARAP binding module drives the pro-autophagic potential of the AML-associated NPM1c variant |
| title_sort | atypical gabarap binding module drives the pro autophagic potential of the aml associated npm1c variant |
| topic | CP: Cancer CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723014961 |
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