|
Protein Kinase C Controls Lysosome Biogenesis Independently of mTORC1
Yang Li, Meng Xu, Xiao Ding, Chen Yan, Zhiqin Song, Lianwan Chen, Xiahe Huang, Xin Wang, Youli Jian, Guihua Tang, Changyong Tang, Yingtong Di, Shuzhen Mu, Xuezhao Liu, Kai Liu, Ting Li, Yingchun Wang, Long Miao, Weixiang Guo, Xiaojiang Hao, and Chonglin Yang
Nature Cell Biology
Abstract
Lysosomes respond to environmental cues by controlling their own biogenesis, but the underlying mechanisms are poorly understood. Here we describe a protein kinase C (PKC)-dependent and mTORC1-independent mechanism for regulating lysosome biogenesis, which provides insights into previously reported effects of PKC on lysosomes. By identifying lysosome-inducing compounds we show that PKC couples activation of the TFEB transcription factor with inactivation of the ZKSCAN3 transcriptional repressor through two parallel signalling cascades. Activated PKC inactivates GSK3β, leading to reduced phosphorylation, nuclear translocation and activation of TFEB, while PKC activates JNK and p38 MAPK, which phosphorylate ZKSCAN3, leading to its inactivation by translocation out of the nucleus. PKC activation may therefore mediate lysosomal adaptation to many extracellular cues. PKC activators facilitate clearance of aggregated proteins and lipid droplets in cell models and ameliorate amyloid β plaque formation in APP/PS1 mouse brains. Thus, PKC activators are viable treatment options for lysosome-related disorders.
|
论文编号: |
DOI:10.1038/ncb3407 |
论文题目: |
Protein Kinase C Controls Lysosome Biogenesis Independently of mTORC1 |
英文论文题目: |
Protein Kinase C Controls Lysosome Biogenesis Independently of mTORC1 |
第一作者: |
Yang Li, Meng Xu, Xiao Ding, Chen Yan, Zhiqin Song, Lianwan Chen, Xiahe Huang, Xin Wang, Youli Jian, Guihua Tang, Changyong Tang, Yingtong Di, Shuzhen Mu, Xuezhao Liu, Kai Liu, Ting Li, Yingchun Wang, Long Miao, Weixiang Guo, Xiaojiang Hao, and Chonglin Yang |
英文第一作者: |
Yang Li, Meng Xu, Xiao Ding, Chen Yan, Zhiqin Song, Lianwan Chen, Xiahe Huang, Xin Wang, Youli Jian, Guihua Tang, Changyong Tang, Yingtong Di, Shuzhen Mu, Xuezhao Liu, Kai Liu, Ting Li, Yingchun Wang, Long Miao, Weixiang Guo, Xiaojiang Hao, and Chonglin Yang |
联系作者: |
|
英文联系作者: |
|
外单位作者单位: |
|
英文外单位作者单位: |
|
发表年度: |
2016-09-13 |
卷: |
|
期: |
|
页码: |
|
摘要: |
Lysosomes respond to environmental cues by controlling their own biogenesis, but the underlying mechanisms are poorly understood. Here we describe a protein kinase C (PKC)-dependent and mTORC1-independent mechanism for regulating lysosome biogenesis, which provides insights into previously reported effects of PKC on lysosomes. By identifying lysosome-inducing compounds we show that PKC couples activation of the TFEB transcription factor with inactivation of the ZKSCAN3 transcriptional repressor through two parallel signalling cascades. Activated PKC inactivates GSK3β, leading to reduced phosphorylation, nuclear translocation and activation of TFEB, while PKC activates JNK and p38 MAPK, which phosphorylate ZKSCAN3, leading to its inactivation by translocation out of the nucleus. PKC activation may therefore mediate lysosomal adaptation to many extracellular cues. PKC activators facilitate clearance of aggregated proteins and lipid droplets in cell models and ameliorate amyloid β plaque formation in APP/PS1 mouse brains. Thus, PKC activators are viable treatment options for lysosome-related disorders. |
英文摘要: |
Lysosomes respond to environmental cues by controlling their own biogenesis, but the underlying mechanisms are poorly understood. Here we describe a protein kinase C (PKC)-dependent and mTORC1-independent mechanism for regulating lysosome biogenesis, which provides insights into previously reported effects of PKC on lysosomes. By identifying lysosome-inducing compounds we show that PKC couples activation of the TFEB transcription factor with inactivation of the ZKSCAN3 transcriptional repressor through two parallel signalling cascades. Activated PKC inactivates GSK3β, leading to reduced phosphorylation, nuclear translocation and activation of TFEB, while PKC activates JNK and p38 MAPK, which phosphorylate ZKSCAN3, leading to its inactivation by translocation out of the nucleus. PKC activation may therefore mediate lysosomal adaptation to many extracellular cues. PKC activators facilitate clearance of aggregated proteins and lipid droplets in cell models and ameliorate amyloid β plaque formation in APP/PS1 mouse brains. Thus, PKC activators are viable treatment options for lysosome-related disorders. |
刊物名称: |
Nature Cell Biology |
英文刊物名称: |
Nature Cell Biology |
论文全文: |
|
英文论文全文: |
|
全文链接: |
|
其它备注: |
Yang Li, Meng Xu, Xiao Ding, Chen Yan, Zhiqin Song, Lianwan Chen, Xiahe Huang, Xin Wang, Youli Jian, Guihua Tang, Changyong Tang, Yingtong Di, Shuzhen Mu, Xuezhao Liu, Kai Liu, Ting Li, Yingchun Wang, Long Miao, Weixiang Guo, Xiaojiang Hao, and Chonglin Yang. Protein Kinase C Controls Lysosome Biogenesis Independently of mTORC1. Nature Cell Biology. DOI:10.1038/ncb3407 |
英文其它备注: |
|
学科: |
|
英文学科: |
|
影响因子: |
|
第一作者所在部门: |
|
英文第一作者所在部门: |
|
论文出处: |
|
英文论文出处: |
|
论文类别: |
|
英文论文类别: |
|
参与作者: |
|
英文参与作者: |
|
|