NEDD4L downregulates autophagy and cell growth by modulating ULK1 and a glutamine transporter
Identifieur interne : 000092 ( Pmc/Checkpoint ); précédent : 000091; suivant : 000093NEDD4L downregulates autophagy and cell growth by modulating ULK1 and a glutamine transporter
Auteurs : Dong-Eun Lee ; Ju Eun Yoo ; Jiyea Kim ; Seungki Kim ; Sunshin Kim ; Ho Lee ; Heesun CheongSource :
- Cell Death & Disease [ 2041-4889 ] ; 2020.
Abstract
In mammals, autophagosome formation is initiated by ULK1 via the posttranslational modification of this protein. However, the precise role of ULK1 ubiquitination in modulating autophagy is unknown. Here, we show that NEDD4L, an E3 ubiquitin ligase, binds ULK1 in pancreatic cancer cells. ULK1 expression was stabilized in NEDD4L knockdown cells compared to that in control cells, suggesting that NEDD4L is involved in ULK1 ubiquitination and its subsequent degradation. Autophagy activity was enhanced in NEDD4L knockdown cells compared to control cells. NEDD4L-depleted cells exhibited an increase in the cellular oxygen consumption rate (OCR) and mitochondrial membrane potential, and maintained mitochondrial fusion status in response to metabolic stress. Enhanced OCR and mitochondrial fusion morphology in NEDD4L knockdown cells were repressed by siRNA targeting ULK1. In addition to ULK1, ASCT2, a glutamine transporter, was accumulated in NEDD4L-depleted cells; this is important for maintaining autophagy activation and mitochondrial metabolic function. Finally, the cellular growth and survival rate increased in NEDD4L knockdown cells compared to control cells. However, the genetic or pharmacological blockade of either ULK1 or ASCT2 in NEDD4L-depleted cells sensitized pancreatic cancer cells, particularly in response to nutrient deprivation. In a mouse xenograft model of pancreatic cancer, the use of autophagy inhibitors suppressed tumor growth more in NEDD4L-depleted cells than in tumors from control cells. NEDD4L and ULK1 levels were inversely correlated in two different pancreatic cancer mouse models-xenograft mouse and KPC mouse models. These results suggest that NEDD4L suppressed autophagy and mitochondrial metabolism by reducing cellular ULK1 or ASCT2 levels, and thus could repress the growth and survival of pancreatic cancer cells. Therefore, ubiquitin ligase-mediated autophagy plays a critical role in regulating mitochondrial metabolism, thereby contributing to the growth and survival of certain cancers with low NEDD4L levels.
Url:
DOI: 10.1038/s41419-020-2242-5
PubMed: 31959741
PubMed Central: 6971022
Affiliations:
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<front><div type="abstract" xml:lang="en"><p id="Par1">In mammals, autophagosome formation is initiated by ULK1 via the posttranslational modification of this protein. However, the precise role of ULK1 ubiquitination in modulating autophagy is unknown. Here, we show that NEDD4L, an E3 ubiquitin ligase, binds ULK1 in pancreatic cancer cells. ULK1 expression was stabilized in NEDD4L knockdown cells compared to that in control cells, suggesting that NEDD4L is involved in ULK1 ubiquitination and its subsequent degradation. Autophagy activity was enhanced in NEDD4L knockdown cells compared to control cells. NEDD4L-depleted cells exhibited an increase in the cellular oxygen consumption rate (OCR) and mitochondrial membrane potential, and maintained mitochondrial fusion status in response to metabolic stress. Enhanced OCR and mitochondrial fusion morphology in NEDD4L knockdown cells were repressed by siRNA targeting ULK1. In addition to ULK1, ASCT2, a glutamine transporter, was accumulated in NEDD4L-depleted cells; this is important for maintaining autophagy activation and mitochondrial metabolic function. Finally, the cellular growth and survival rate increased in NEDD4L knockdown cells compared to control cells. However, the genetic or pharmacological blockade of either ULK1 or ASCT2 in NEDD4L-depleted cells sensitized pancreatic cancer cells, particularly in response to nutrient deprivation. In a mouse xenograft model of pancreatic cancer, the use of autophagy inhibitors suppressed tumor growth more in NEDD4L-depleted cells than in tumors from control cells. NEDD4L and ULK1 levels were inversely correlated in two different pancreatic cancer mouse models-xenograft mouse and KPC mouse models. These results suggest that NEDD4L suppressed autophagy and mitochondrial metabolism by reducing cellular ULK1 or ASCT2 levels, and thus could repress the growth and survival of pancreatic cancer cells. Therefore, ubiquitin ligase-mediated autophagy plays a critical role in regulating mitochondrial metabolism, thereby contributing to the growth and survival of certain cancers with low NEDD4L levels.</p>
</div>
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<biblStruct><analytic><author><name sortKey="Choi, Dw" uniqKey="Choi D">DW Choi</name>
</author>
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<biblStruct><analytic><author><name sortKey="Hingorani, Sr" uniqKey="Hingorani S">SR Hingorani</name>
</author>
</analytic>
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</TEI>
<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Cell Death Dis</journal-id>
<journal-id journal-id-type="iso-abbrev">Cell Death Dis</journal-id>
<journal-title-group><journal-title>Cell Death & Disease</journal-title>
</journal-title-group>
<issn pub-type="epub">2041-4889</issn>
<publisher><publisher-name>Nature Publishing Group UK</publisher-name>
<publisher-loc>London</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">31959741</article-id>
<article-id pub-id-type="pmc">6971022</article-id>
<article-id pub-id-type="publisher-id">2242</article-id>
<article-id pub-id-type="doi">10.1038/s41419-020-2242-5</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>NEDD4L downregulates autophagy and cell growth by modulating ULK1 and a glutamine transporter</article-title>
</title-group>
<contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Lee</surname>
<given-names>Dong-Eun</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="yes"><name><surname>Yoo</surname>
<given-names>Ju Eun</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kim</surname>
<given-names>Jiyea</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kim</surname>
<given-names>Seungki</given-names>
</name>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kim</surname>
<given-names>Sunshin</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lee</surname>
<given-names>Ho</given-names>
</name>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0003-1946-107X</contrib-id>
<name><surname>Cheong</surname>
<given-names>Heesun</given-names>
</name>
<address><email>heesunch@ncc.re.kr</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<aff id="Aff1"><label>1</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 9810</institution-id>
<institution-id institution-id-type="GRID">grid.410914.9</institution-id>
<institution>Research Institute, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu,</institution>
</institution-wrap>
Goyang-Si, Gyeonggi-Do Republic of Korea</aff>
<aff id="Aff2"><label>2</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 9810</institution-id>
<institution-id institution-id-type="GRID">grid.410914.9</institution-id>
<institution>Department of Cancer Biomedical Science,</institution>
<institution>Graduate School of Cancer Science & Policy, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu,</institution>
</institution-wrap>
Goyang-Si, Gyeonggi-Do Republic of Korea</aff>
</contrib-group>
<pub-date pub-type="epub"><day>20</day>
<month>1</month>
<year>2020</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>20</day>
<month>1</month>
<year>2020</year>
</pub-date>
<pub-date pub-type="collection"><month>1</month>
<year>2020</year>
</pub-date>
<volume>11</volume>
<issue>1</issue>
<elocation-id>38</elocation-id>
<history><date date-type="received"><day>24</day>
<month>9</month>
<year>2019</year>
</date>
<date date-type="rev-recd"><day>30</day>
<month>12</month>
<year>2019</year>
</date>
<date date-type="accepted"><day>8</day>
<month>1</month>
<year>2020</year>
</date>
</history>
<permissions><copyright-statement>© The Author(s) 2020</copyright-statement>
<license license-type="OpenAccess"><license-p><bold>Open Access</bold>
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
.</license-p>
</license>
</permissions>
<abstract id="Abs1"><p id="Par1">In mammals, autophagosome formation is initiated by ULK1 via the posttranslational modification of this protein. However, the precise role of ULK1 ubiquitination in modulating autophagy is unknown. Here, we show that NEDD4L, an E3 ubiquitin ligase, binds ULK1 in pancreatic cancer cells. ULK1 expression was stabilized in NEDD4L knockdown cells compared to that in control cells, suggesting that NEDD4L is involved in ULK1 ubiquitination and its subsequent degradation. Autophagy activity was enhanced in NEDD4L knockdown cells compared to control cells. NEDD4L-depleted cells exhibited an increase in the cellular oxygen consumption rate (OCR) and mitochondrial membrane potential, and maintained mitochondrial fusion status in response to metabolic stress. Enhanced OCR and mitochondrial fusion morphology in NEDD4L knockdown cells were repressed by siRNA targeting ULK1. In addition to ULK1, ASCT2, a glutamine transporter, was accumulated in NEDD4L-depleted cells; this is important for maintaining autophagy activation and mitochondrial metabolic function. Finally, the cellular growth and survival rate increased in NEDD4L knockdown cells compared to control cells. However, the genetic or pharmacological blockade of either ULK1 or ASCT2 in NEDD4L-depleted cells sensitized pancreatic cancer cells, particularly in response to nutrient deprivation. In a mouse xenograft model of pancreatic cancer, the use of autophagy inhibitors suppressed tumor growth more in NEDD4L-depleted cells than in tumors from control cells. NEDD4L and ULK1 levels were inversely correlated in two different pancreatic cancer mouse models-xenograft mouse and KPC mouse models. These results suggest that NEDD4L suppressed autophagy and mitochondrial metabolism by reducing cellular ULK1 or ASCT2 levels, and thus could repress the growth and survival of pancreatic cancer cells. Therefore, ubiquitin ligase-mediated autophagy plays a critical role in regulating mitochondrial metabolism, thereby contributing to the growth and survival of certain cancers with low NEDD4L levels.</p>
</abstract>
<kwd-group kwd-group-type="npg-subject"><title>Subject terms</title>
<kwd>Tumour-suppressor proteins</kwd>
<kwd>Macroautophagy</kwd>
</kwd-group>
<funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/501100003725</institution-id>
<institution>National Research Foundation of Korea (NRF)</institution>
</institution-wrap>
</funding-source>
<award-id>NRF-2017R1A2B4011732</award-id>
<award-id>NRF-2017R1A2B4011732</award-id>
<award-id>NRF-2017R1A2B4011732</award-id>
<principal-award-recipient><name><surname>Lee</surname>
<given-names>Dong-Eun</given-names>
</name>
<name><surname>Kim</surname>
<given-names>Jiyea</given-names>
</name>
<name><surname>Cheong</surname>
<given-names>Heesun</given-names>
</name>
</principal-award-recipient>
</award-group>
</funding-group>
<funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/501100003645</institution-id>
<institution>National Cancer Center (NCC)</institution>
</institution-wrap>
</funding-source>
<award-id>1731230</award-id>
<principal-award-recipient><name><surname>Cheong</surname>
<given-names>Heesun</given-names>
</name>
</principal-award-recipient>
</award-group>
</funding-group>
<funding-group><award-group><funding-source><institution>National Cancer Center Korea, Intramural Research Grant 1731230</institution>
</funding-source>
</award-group>
</funding-group>
<custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name>
<meta-value>© The Author(s) 2020</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
</pmc>
<affiliations><list></list>
<tree><noCountry><name sortKey="Cheong, Heesun" sort="Cheong, Heesun" uniqKey="Cheong H" first="Heesun" last="Cheong">Heesun Cheong</name>
<name sortKey="Kim, Jiyea" sort="Kim, Jiyea" uniqKey="Kim J" first="Jiyea" last="Kim">Jiyea Kim</name>
<name sortKey="Kim, Seungki" sort="Kim, Seungki" uniqKey="Kim S" first="Seungki" last="Kim">Seungki Kim</name>
<name sortKey="Kim, Sunshin" sort="Kim, Sunshin" uniqKey="Kim S" first="Sunshin" last="Kim">Sunshin Kim</name>
<name sortKey="Lee, Dong Eun" sort="Lee, Dong Eun" uniqKey="Lee D" first="Dong-Eun" last="Lee">Dong-Eun Lee</name>
<name sortKey="Lee, Ho" sort="Lee, Ho" uniqKey="Lee H" first="Ho" last="Lee">Ho Lee</name>
<name sortKey="Yoo, Ju Eun" sort="Yoo, Ju Eun" uniqKey="Yoo J" first="Ju Eun" last="Yoo">Ju Eun Yoo</name>
</noCountry>
</tree>
</affiliations>
</record>
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