AMBRA1 Negatively Regulates the Function of ALDH1B1, a Cancer Stem Cell Marker, by Controlling Its Ubiquitination

Activating molecule in Beclin-1-regulated autophagy (AMBRA1), a negative regulator of tumorigenesis, is a substrate receptor of the ubiquitin conjugation system. ALDH1B1, an aldehyde dehydrogenase, is a cancer stem cell (CSC) marker that is required for carcinogenesis via upregulation of the β-caten...

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Autores principales:	Seung-Heon Baek, Yeun-Kyu Jang
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	colorectal cancer stem cell E3 ubiquitin ligase substrate receptor aldehyde dehydrogenase 1B1 noncanonical ubiquitination Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/0e25652bbdcc44d8aa654b69820a1d73
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spelling	oai:doaj.org-article:0e25652bbdcc44d8aa654b69820a1d732021-11-11T17:28:10ZAMBRA1 Negatively Regulates the Function of ALDH1B1, a Cancer Stem Cell Marker, by Controlling Its Ubiquitination10.3390/ijms2221120791422-00671661-6596https://doaj.org/article/0e25652bbdcc44d8aa654b69820a1d732021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/12079https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Activating molecule in Beclin-1-regulated autophagy (AMBRA1), a negative regulator of tumorigenesis, is a substrate receptor of the ubiquitin conjugation system. ALDH1B1, an aldehyde dehydrogenase, is a cancer stem cell (CSC) marker that is required for carcinogenesis via upregulation of the β-catenin pathway. Although accumulating evidence suggests a role for ubiquitination in the regulation of CSC markers, the ubiquitination-mediated regulation of ALDH1B1 has not been unraveled. While proteome analysis has suggested that AMBRA1 and ALDH1B1 can interact, their interaction has not been validated. Here, we show that AMBRA1 is a negative regulator of ALDH1B1. The expression of ALDH1B1-regulated genes, including <i>PTEN</i>, <i>CTNNB1</i> (β-catenin), and CSC-related β-catenin target genes, is inversely regulated by AMBRA1, suggesting a negative regulatory role of AMBRA1 in the expression of ALDH1B1-regulated genes. We found that the K27- and K33-linked ubiquitination of ALDH1B1 is mediated via the cooperation of AMBRA1 with other E3 ligases, such as TRAF6. Importantly, ubiquitination site mapping revealed that K506, K511, and K515 are important for the K27-linked ubiquitination of ALDH1B1, while K33-linked ubiquitination occurs at K506. A ubiquitination-defective mutant of ALDH1B1 increased the self-association ability of ALDH1B1, suggesting a negative correlation between the ubiquitination and self-association of ALDH1B1. Together, our findings indicate that ALDH1B1 is negatively regulated by AMBRA1-mediated noncanonical ubiquitination.Seung-Heon BaekYeun-Kyu JangMDPI AGarticlecolorectal cancer stem cellE3 ubiquitin ligasesubstrate receptoraldehyde dehydrogenase 1B1noncanonical ubiquitinationBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12079, p 12079 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	colorectal cancer stem cell E3 ubiquitin ligase substrate receptor aldehyde dehydrogenase 1B1 noncanonical ubiquitination Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	colorectal cancer stem cell E3 ubiquitin ligase substrate receptor aldehyde dehydrogenase 1B1 noncanonical ubiquitination Biology (General) QH301-705.5 Chemistry QD1-999 Seung-Heon Baek Yeun-Kyu Jang AMBRA1 Negatively Regulates the Function of ALDH1B1, a Cancer Stem Cell Marker, by Controlling Its Ubiquitination
description	Activating molecule in Beclin-1-regulated autophagy (AMBRA1), a negative regulator of tumorigenesis, is a substrate receptor of the ubiquitin conjugation system. ALDH1B1, an aldehyde dehydrogenase, is a cancer stem cell (CSC) marker that is required for carcinogenesis via upregulation of the β-catenin pathway. Although accumulating evidence suggests a role for ubiquitination in the regulation of CSC markers, the ubiquitination-mediated regulation of ALDH1B1 has not been unraveled. While proteome analysis has suggested that AMBRA1 and ALDH1B1 can interact, their interaction has not been validated. Here, we show that AMBRA1 is a negative regulator of ALDH1B1. The expression of ALDH1B1-regulated genes, including <i>PTEN</i>, <i>CTNNB1</i> (β-catenin), and CSC-related β-catenin target genes, is inversely regulated by AMBRA1, suggesting a negative regulatory role of AMBRA1 in the expression of ALDH1B1-regulated genes. We found that the K27- and K33-linked ubiquitination of ALDH1B1 is mediated via the cooperation of AMBRA1 with other E3 ligases, such as TRAF6. Importantly, ubiquitination site mapping revealed that K506, K511, and K515 are important for the K27-linked ubiquitination of ALDH1B1, while K33-linked ubiquitination occurs at K506. A ubiquitination-defective mutant of ALDH1B1 increased the self-association ability of ALDH1B1, suggesting a negative correlation between the ubiquitination and self-association of ALDH1B1. Together, our findings indicate that ALDH1B1 is negatively regulated by AMBRA1-mediated noncanonical ubiquitination.
format	article
author	Seung-Heon Baek Yeun-Kyu Jang
author_facet	Seung-Heon Baek Yeun-Kyu Jang
author_sort	Seung-Heon Baek
title	AMBRA1 Negatively Regulates the Function of ALDH1B1, a Cancer Stem Cell Marker, by Controlling Its Ubiquitination
title_short	AMBRA1 Negatively Regulates the Function of ALDH1B1, a Cancer Stem Cell Marker, by Controlling Its Ubiquitination
title_full	AMBRA1 Negatively Regulates the Function of ALDH1B1, a Cancer Stem Cell Marker, by Controlling Its Ubiquitination
title_fullStr	AMBRA1 Negatively Regulates the Function of ALDH1B1, a Cancer Stem Cell Marker, by Controlling Its Ubiquitination
title_full_unstemmed	AMBRA1 Negatively Regulates the Function of ALDH1B1, a Cancer Stem Cell Marker, by Controlling Its Ubiquitination
title_sort	ambra1 negatively regulates the function of aldh1b1, a cancer stem cell marker, by controlling its ubiquitination
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/0e25652bbdcc44d8aa654b69820a1d73
work_keys_str_mv	AT seungheonbaek ambra1negativelyregulatesthefunctionofaldh1b1acancerstemcellmarkerbycontrollingitsubiquitination AT yeunkyujang ambra1negativelyregulatesthefunctionofaldh1b1acancerstemcellmarkerbycontrollingitsubiquitination
_version_	1718432044706430976

AMBRA1 Negatively Regulates the Function of ALDH1B1, a Cancer Stem Cell Marker, by Controlling Its Ubiquitination

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