CDK4/6 regulate lysosome biogenesis through TFEB/TFE3
Lysosomes are degradation and signaling organelles that adapt their biogenesis to meet many different cellular demands; however, it is unknown how lysosomes change their numbers for cell division. Here, we report that the cyclin-dependent kinases CDK4/6 regulate lysosome biogenesis during the cell c...
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Veröffentlicht in: | The Journal of cell biology 2020-08, Vol.219 (8) |
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container_title | The Journal of cell biology |
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creator | Yin, Qiuyuan Jian, Youli Xu, Meng Huang, Xiahe Wang, Niya Liu, Zhifang Li, Qian Li, Jinglin Zhou, Hejiang Xu, Lin Wang, Yingchun Yang, Chonglin |
description | Lysosomes are degradation and signaling organelles that adapt their biogenesis to meet many different cellular demands; however, it is unknown how lysosomes change their numbers for cell division. Here, we report that the cyclin-dependent kinases CDK4/6 regulate lysosome biogenesis during the cell cycle. Chemical or genetic inactivation of CDK4/6 increases lysosomal numbers by activating the lysosome and autophagy transcription factors TFEB and TFE3. CDK4/6 interact with and phosphorylate TFEB/TFE3 in the nucleus, thereby inactivating them by promoting their shuttling to the cytoplasm. During the cell cycle, lysosome numbers increase in S and G2/M phases when cyclin D turnover diminishes CDK4/6 activity. These findings not only uncover the molecular events that direct the nuclear export of TFEB/TFE3, but also suggest a mechanism that controls lysosome biogenesis in the cell cycle. CDK4/6 inhibitors promote autophagy and lysosome-dependent degradation, which has important implications for the therapy of cancer and lysosome-related disorders. |
doi_str_mv | 10.1083/jcb.201911036 |
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Here, we report that the cyclin-dependent kinases CDK4/6 regulate lysosome biogenesis during the cell cycle. Chemical or genetic inactivation of CDK4/6 increases lysosomal numbers by activating the lysosome and autophagy transcription factors TFEB and TFE3. CDK4/6 interact with and phosphorylate TFEB/TFE3 in the nucleus, thereby inactivating them by promoting their shuttling to the cytoplasm. During the cell cycle, lysosome numbers increase in S and G2/M phases when cyclin D turnover diminishes CDK4/6 activity. These findings not only uncover the molecular events that direct the nuclear export of TFEB/TFE3, but also suggest a mechanism that controls lysosome biogenesis in the cell cycle. CDK4/6 inhibitors promote autophagy and lysosome-dependent degradation, which has important implications for the therapy of cancer and lysosome-related disorders.</description><identifier>ISSN: 0021-9525</identifier><identifier>EISSN: 1540-8140</identifier><identifier>DOI: 10.1083/jcb.201911036</identifier><identifier>PMID: 32662822</identifier><language>eng</language><publisher>United States: Rockefeller University Press</publisher><subject>Active Transport, Cell Nucleus ; Autophagy ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism ; Biochemistry ; Cell Cycle ; Cell Nucleus - enzymology ; Cell Nucleus - genetics ; Cell Proliferation ; Cyclin D1 - metabolism ; Cyclin-Dependent Kinase 4 - genetics ; Cyclin-Dependent Kinase 4 - metabolism ; Cyclin-Dependent Kinase 6 - genetics ; Cyclin-Dependent Kinase 6 - metabolism ; HCT116 Cells ; HeLa Cells ; Hep G2 Cells ; Humans ; Lysosomes - enzymology ; Lysosomes - genetics ; Organelle Biogenesis ; Organelles ; Phosphorylation ; Proteolysis ; Signal Transduction</subject><ispartof>The Journal of cell biology, 2020-08, Vol.219 (8)</ispartof><rights>2020 Yin et al.</rights><rights>2020 Yin et al. 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c453t-e5584b11e14cf4a4ddacaa7ab6f5e2ca967620cbf0e292f8fc47e2f36396e0ae3</citedby><cites>FETCH-LOGICAL-c453t-e5584b11e14cf4a4ddacaa7ab6f5e2ca967620cbf0e292f8fc47e2f36396e0ae3</cites><orcidid>0000-0001-9366-5746 ; 0000-0001-8764-9344 ; 0000-0002-4104-7855</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32662822$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yin, Qiuyuan</creatorcontrib><creatorcontrib>Jian, Youli</creatorcontrib><creatorcontrib>Xu, Meng</creatorcontrib><creatorcontrib>Huang, Xiahe</creatorcontrib><creatorcontrib>Wang, Niya</creatorcontrib><creatorcontrib>Liu, Zhifang</creatorcontrib><creatorcontrib>Li, Qian</creatorcontrib><creatorcontrib>Li, Jinglin</creatorcontrib><creatorcontrib>Zhou, Hejiang</creatorcontrib><creatorcontrib>Xu, Lin</creatorcontrib><creatorcontrib>Wang, Yingchun</creatorcontrib><creatorcontrib>Yang, Chonglin</creatorcontrib><title>CDK4/6 regulate lysosome biogenesis through TFEB/TFE3</title><title>The Journal of cell biology</title><addtitle>J Cell Biol</addtitle><description>Lysosomes are degradation and signaling organelles that adapt their biogenesis to meet many different cellular demands; however, it is unknown how lysosomes change their numbers for cell division. Here, we report that the cyclin-dependent kinases CDK4/6 regulate lysosome biogenesis during the cell cycle. Chemical or genetic inactivation of CDK4/6 increases lysosomal numbers by activating the lysosome and autophagy transcription factors TFEB and TFE3. CDK4/6 interact with and phosphorylate TFEB/TFE3 in the nucleus, thereby inactivating them by promoting their shuttling to the cytoplasm. During the cell cycle, lysosome numbers increase in S and G2/M phases when cyclin D turnover diminishes CDK4/6 activity. These findings not only uncover the molecular events that direct the nuclear export of TFEB/TFE3, but also suggest a mechanism that controls lysosome biogenesis in the cell cycle. CDK4/6 inhibitors promote autophagy and lysosome-dependent degradation, which has important implications for the therapy of cancer and lysosome-related disorders.</description><subject>Active Transport, Cell Nucleus</subject><subject>Autophagy</subject><subject>Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics</subject><subject>Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism</subject><subject>Biochemistry</subject><subject>Cell Cycle</subject><subject>Cell Nucleus - enzymology</subject><subject>Cell Nucleus - genetics</subject><subject>Cell Proliferation</subject><subject>Cyclin D1 - metabolism</subject><subject>Cyclin-Dependent Kinase 4 - genetics</subject><subject>Cyclin-Dependent Kinase 4 - metabolism</subject><subject>Cyclin-Dependent Kinase 6 - genetics</subject><subject>Cyclin-Dependent Kinase 6 - metabolism</subject><subject>HCT116 Cells</subject><subject>HeLa Cells</subject><subject>Hep G2 Cells</subject><subject>Humans</subject><subject>Lysosomes - enzymology</subject><subject>Lysosomes - genetics</subject><subject>Organelle Biogenesis</subject><subject>Organelles</subject><subject>Phosphorylation</subject><subject>Proteolysis</subject><subject>Signal Transduction</subject><issn>0021-9525</issn><issn>1540-8140</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkE1PwkAQhjdGI4gevZoevRRmP9teTBRBjSRe8LzZLtNSUrq425rw761BiV7mPcyTdyYPIdcUxhRSPtnYfMyAZpQCVydkSKWAOKUCTskQgNE4k0wOyEUIGwAQieDnZMCZUixlbEjk9PFVTFTksexq02JU74MLbotRXrkSGwxViNq1d125jpbz2cOkH_ySnBWmDnj1kyPyPp8tp8_x4u3pZXq_iK2QvI1RylTklCIVthBGrFbGGpOYXBUSmTWZShQDmxeALGNFWliRICu44plCMMhH5O7Qu-vyLa4sNq03td75amv8XjtT6f-bplrr0n3qRABNgfYFtz8F3n10GFq9rYLFujYNui5oJhhPsiSDpEfjA2q9C8FjcTxDQX-r1r1qfVTd8zd_fzvSv275F3BjeY8</recordid><startdate>20200803</startdate><enddate>20200803</enddate><creator>Yin, Qiuyuan</creator><creator>Jian, Youli</creator><creator>Xu, Meng</creator><creator>Huang, Xiahe</creator><creator>Wang, Niya</creator><creator>Liu, Zhifang</creator><creator>Li, Qian</creator><creator>Li, Jinglin</creator><creator>Zhou, Hejiang</creator><creator>Xu, Lin</creator><creator>Wang, Yingchun</creator><creator>Yang, Chonglin</creator><general>Rockefeller University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-9366-5746</orcidid><orcidid>https://orcid.org/0000-0001-8764-9344</orcidid><orcidid>https://orcid.org/0000-0002-4104-7855</orcidid></search><sort><creationdate>20200803</creationdate><title>CDK4/6 regulate lysosome biogenesis through TFEB/TFE3</title><author>Yin, Qiuyuan ; Jian, Youli ; Xu, Meng ; Huang, Xiahe ; Wang, Niya ; Liu, Zhifang ; Li, Qian ; Li, Jinglin ; Zhou, Hejiang ; Xu, Lin ; Wang, Yingchun ; Yang, Chonglin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c453t-e5584b11e14cf4a4ddacaa7ab6f5e2ca967620cbf0e292f8fc47e2f36396e0ae3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Active Transport, Cell Nucleus</topic><topic>Autophagy</topic><topic>Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics</topic><topic>Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism</topic><topic>Biochemistry</topic><topic>Cell Cycle</topic><topic>Cell Nucleus - enzymology</topic><topic>Cell Nucleus - genetics</topic><topic>Cell Proliferation</topic><topic>Cyclin D1 - metabolism</topic><topic>Cyclin-Dependent Kinase 4 - genetics</topic><topic>Cyclin-Dependent Kinase 4 - metabolism</topic><topic>Cyclin-Dependent Kinase 6 - genetics</topic><topic>Cyclin-Dependent Kinase 6 - metabolism</topic><topic>HCT116 Cells</topic><topic>HeLa Cells</topic><topic>Hep G2 Cells</topic><topic>Humans</topic><topic>Lysosomes - enzymology</topic><topic>Lysosomes - genetics</topic><topic>Organelle Biogenesis</topic><topic>Organelles</topic><topic>Phosphorylation</topic><topic>Proteolysis</topic><topic>Signal Transduction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yin, Qiuyuan</creatorcontrib><creatorcontrib>Jian, Youli</creatorcontrib><creatorcontrib>Xu, Meng</creatorcontrib><creatorcontrib>Huang, Xiahe</creatorcontrib><creatorcontrib>Wang, Niya</creatorcontrib><creatorcontrib>Liu, Zhifang</creatorcontrib><creatorcontrib>Li, Qian</creatorcontrib><creatorcontrib>Li, Jinglin</creatorcontrib><creatorcontrib>Zhou, Hejiang</creatorcontrib><creatorcontrib>Xu, Lin</creatorcontrib><creatorcontrib>Wang, Yingchun</creatorcontrib><creatorcontrib>Yang, Chonglin</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of cell biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yin, Qiuyuan</au><au>Jian, Youli</au><au>Xu, Meng</au><au>Huang, Xiahe</au><au>Wang, Niya</au><au>Liu, Zhifang</au><au>Li, Qian</au><au>Li, Jinglin</au><au>Zhou, Hejiang</au><au>Xu, Lin</au><au>Wang, Yingchun</au><au>Yang, Chonglin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>CDK4/6 regulate lysosome biogenesis through TFEB/TFE3</atitle><jtitle>The Journal of cell biology</jtitle><addtitle>J Cell Biol</addtitle><date>2020-08-03</date><risdate>2020</risdate><volume>219</volume><issue>8</issue><issn>0021-9525</issn><eissn>1540-8140</eissn><abstract>Lysosomes are degradation and signaling organelles that adapt their biogenesis to meet many different cellular demands; however, it is unknown how lysosomes change their numbers for cell division. Here, we report that the cyclin-dependent kinases CDK4/6 regulate lysosome biogenesis during the cell cycle. Chemical or genetic inactivation of CDK4/6 increases lysosomal numbers by activating the lysosome and autophagy transcription factors TFEB and TFE3. CDK4/6 interact with and phosphorylate TFEB/TFE3 in the nucleus, thereby inactivating them by promoting their shuttling to the cytoplasm. During the cell cycle, lysosome numbers increase in S and G2/M phases when cyclin D turnover diminishes CDK4/6 activity. These findings not only uncover the molecular events that direct the nuclear export of TFEB/TFE3, but also suggest a mechanism that controls lysosome biogenesis in the cell cycle. CDK4/6 inhibitors promote autophagy and lysosome-dependent degradation, which has important implications for the therapy of cancer and lysosome-related disorders.</abstract><cop>United States</cop><pub>Rockefeller University Press</pub><pmid>32662822</pmid><doi>10.1083/jcb.201911036</doi><orcidid>https://orcid.org/0000-0001-9366-5746</orcidid><orcidid>https://orcid.org/0000-0001-8764-9344</orcidid><orcidid>https://orcid.org/0000-0002-4104-7855</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Active Transport, Cell Nucleus Autophagy Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism Biochemistry Cell Cycle Cell Nucleus - enzymology Cell Nucleus - genetics Cell Proliferation Cyclin D1 - metabolism Cyclin-Dependent Kinase 4 - genetics Cyclin-Dependent Kinase 4 - metabolism Cyclin-Dependent Kinase 6 - genetics Cyclin-Dependent Kinase 6 - metabolism HCT116 Cells HeLa Cells Hep G2 Cells Humans Lysosomes - enzymology Lysosomes - genetics Organelle Biogenesis Organelles Phosphorylation Proteolysis Signal Transduction |
title | CDK4/6 regulate lysosome biogenesis through TFEB/TFE3 |
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