Article
Multidisciplinary Sciences
Delong Meng, Qianmei Yang, Mi-Hyeon Jeong, Adna Curukovic, Shweta Tiwary, Chase H. Melick, Tshering D. Lama-Sherpa, Huanyu Wang, Mariela Huerta-Rosario, Greg Urquhart, Lauren G. Zacharias, Cheryl Lewis, Ralph J. DeBerardinis, Jenna L. Jewell
Summary: SNAT7 activates mTORC1 by mediating the macropinocytosis of extracellular proteins independently of Rag GTPase. It plays a crucial regulatory role in mTORC1 activation and is essential for sustaining KRAS-driven pancreatic cancer cell growth.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Multidisciplinary Sciences
Clement Bodineau, Mercedes Tome, Sarah Courtois, Ana S. H. Costa, Marco Sciacovelli, Benoit Rousseau, Elodie Richard, Pierre Vacher, Carlos Parejo-Perez, Emilie Bessede, Christine Varon, Pierre Soubeyran, Christian Frezza, Piedad del Socorro Murdoch, Victor H. Villar, Raul Duran
Summary: In this study, the authors demonstrate that reactivation of AMPK can inhibit glutamine-dependent activation of mTORC1 and glutamoptosis, revealing a dual metabolic connection between glutamine metabolism and mTORC1 through two pathways. This finding has significant implications for the design of future therapeutic strategies for diseases such as cancer.
NATURE COMMUNICATIONS
(2021)
Article
Cell Biology
Guokai Yan, Xiuzhi Li, Zilong Zheng, Weihua Gao, Changqing Chen, Xinkai Wang, Zhongyi Cheng, Jie Yu, Geng Zou, Muhammad Zahid Farooq, Xiaoyan Zhu, Weiyun Zhu, Qing Zhong, Xianghua Yan
Summary: In this study, a cell-free system was established to mimic the activation of MTORC1, and CANX was identified as an essential regulator for leucine-stimulated MTORC1 pathway. CANX was found to translocate to lysosomes after leucine deprivation, and its interaction with LAMP2 was required to inhibit Ragulator activity toward RRAG GTPases. Moreover, the crotonylation of CANX at lysine (K) 525 was promoted by leucine deprivation, and KAT7 was identified as the enzyme responsible for this modification. These findings provide new insights into the regulatory mechanism of the leucine-stimulated MTORC1 pathway.
Editorial Material
Cell Biology
Sangam Rajak, Paul M. Yen, Rohit A. Sinha
Summary: Crinophagy, the intracellular degradation of hormone-containing secretory vesicles by lysosomes, plays a critical role in regulating hormone secretion. Inhibition of MTORC1 induces crinophagy-mediated degradation of glucagon, leading to decreased secretion in response to hypoglycemia, suggesting that modulating crinophagy could be a novel therapeutic strategy for endocrine and metabolic disorders.
Article
Endocrinology & Metabolism
Tal Israeli, Yael Riahi, Perla Garzon, Ruy Andrade Louzada, Joao Pedro Werneck-de-Castro, Manuel Blandino-Rosano, Roni Yeroslaviz-Stolper, Liat Kadosh, Sharona Tornovsky-Babeay, Gilad Hacker, Nitzan Israeli, Orly Agmon, Boaz Tirosh, Erol Cerasi, Ernesto Bernal-Mizrachi, Gil Leibowitz
Summary: The regulation of autophagy in beta-cells by mTORC1 plays a crucial role in insulin secretion and glucose homeostasis. Fasting inhibits mTORC1 and stimulates autophagy to maintain low insulin levels and prevent hypoglycemia. However, elevated leucine and glucose levels activate mTORC1 and inhibit autophagy, which may contribute to hyper-insulinemia commonly observed in obesity.
Article
Cell Biology
Terytty Yang Li, Qi Wang, Arwen W. Gao, Xiaoxu Li, Yu Sun, Adrienne Mottis, Minho Shong, Johan Auwerx
Summary: Lysosomal acidification through v-ATPase is crucial for the transcriptional activation of the mitochondrial unfolded protein response (UPRmt). The activation of lysosomes by v-ATPase stimulates mTORC1, which then phosphorylates the transcription factor ATF4, leading to the activation of the UPRmt and mitochondrial function resilience.
Article
Microbiology
Yanan Fu, Zhen Fu, Zhelin Su, Lisha Li, Yilin Yang, Yubei Tan, Yixin Xiang, Yuejun Shi, Shengsong Xie, Limeng Sun, Guiqing Peng
Summary: mLST8 is identified as a critical host regulator of CoV replication, and its knockout promotes autophagy activation and inhibits CoV replication. This study reveals the mechanism of CoV replication and provides new insights for the development of broad-spectrum antiviral drugs.
Article
Multidisciplinary Sciences
Rachel M. Jansen, Roberta Peruzzo, Simon A. Fromm, Adam L. Yokom, Roberto Zoncu, James H. Hurley
Summary: The cryo-electron microscopy structure of the active FLCN complex provides insights into the regulation of cell growth and metabolism by mTORC1 pathways. The study reveals the important role of FLCN in controlling mTORC1 phosphorylation of key substrates and suggests new possibilities for developing selective mTORC1 antagonists.
Article
Multidisciplinary Sciences
Yui Kotani, Mami Sumiyoshi, Megumi Sasada, Toshio Watanabe, Satoshi Matsuda
Summary: This study reveals that Arf1 plays an important role in the activation of mTORC1 and cell proliferation in mast cells, but has little impact on degranulation and cytokine secretion. This finding suggests the potential of Arf1 as a therapeutic target for mast cell proliferative disorders.
SCIENTIFIC REPORTS
(2022)
Article
Cell Biology
Wen Li, Yulan Li, Yetong Guan, Yingxin Du, Mingsheng Zhao, Xiaotong Chen, Faliang Zhu, Chun Guo, Yufeng Jia, Yuan Li, Xiaoyu Wang, Xiaoyan Wang, Yongyu Shi, Qun Wang, Yan Li, Lining Zhang
Summary: Autophagy is a conserved evolutionary process closely integrated with the immune system to modulate immune responses through cell signaling pathways. TNFAIP8L2, a newly identified immune negative regulator, plays a crucial role in regulating autophagy by interacting with RAC1-MTORC1 axis.
Article
Nutrition & Dietetics
Qihui Li, Jiaming Chen, Jiaxin Liu, Tongbin Lin, Xinghong Liu, Shuchang Zhang, Xianhuai Yue, Xiaoli Zhang, Xiangfang Zeng, Man Ren, Wutai Guan, Shihai Zhang
Summary: This study identifies glutamine and leucine as the amino acids that have the greatest impact on milk synthesis. They regulate milk synthesis through the activation of G-protein-coupled receptors (GPCRs) signaling pathway. The study also highlights the important role of the GPCR CaSR in mammary epithelial cells, which works together with glutamine and leucine to promote milk synthesis through the mTORC1 signaling pathway.
EUROPEAN JOURNAL OF NUTRITION
(2023)
Article
Multidisciplinary Sciences
Hong-Wen Tang, Jui-Hsia Weng, Wen Xing Lee, Yanhui Hu, Lei Gu, Sungyun Cho, Gina Lee, Richard Binari, Cathleen Li, Min En Cheng, Ah-Ram Kim, Jun Xu, Zhangfei Shen, Chiwei Xu, John M. Asara, John Blenis, Norbert Perrimon
Summary: mTORC1 is a central regulator of cell growth and metabolism, playing critical roles in RNA biogenesis and processing. The study demonstrates that mTORC1 activates the chaperonin CCT complex to stabilize MTC, thereby increasing m(6)A levels and suppressing autophagy by degrading autophagy-related genes.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Food Science & Technology
GuoYan Wang, Lei Chen, SenLin Qin, HuiJun Geng, Chao Xia, YiNing Zheng, XinJian Lei, Jun Zhang, ShengRu Wu, JunHu Yao, Lu Deng
Summary: This study reveals that chenodeoxycholic acid (CDCA) and farnesoid X receptor (FXR) can activate the mTORC1 pathway, promote lysosomal translocation and activation of mTORC1, and inhibit cellular autophagy. It suggests that decreasing SESN2 expression and activating the mTORC1 pathway could be potential therapeutic targets for enterohepatic and metabolic disorders.
MOLECULAR NUTRITION & FOOD RESEARCH
(2023)
Article
Oncology
Chen Wang, Wei Wang, Xiaodan Han, Longxia Du, Aili Li, Guojin Huang
Summary: The study reveals that METTL1 is upregulated in LUAD tissues and associated with unfavorable prognosis, promoting proliferation and colony formation of A549 cells while inhibiting autophagy. It suggests that METTL1 acts as an oncogene in LUAD and may be a potential prognostic predictor and therapeutic target.
Editorial Material
Cell Biology
Lan Jiang, Tianyun Shen, Xinyuan Wang, Lunzhi Dai, Kefeng Lu, Huihui Li
Summary: Posttranslational modification plays a crucial role in regulating protein functions. The functions and mechanisms of N-terminal acetylation, which occurs on the first amino acids of proteins, in the field of macroautophagy/autophagy are not well understood. Recent studies have shown that the N-terminal acetyltransferase NatB is essential for autophagy and it modifies actin cytoskeleton constituent Act1 and dynamin-like GTPase Vps1, promoting the formation and fusion of autophagosomes.
Review
Biochemistry & Molecular Biology
Sung Min Son, So Jung Park, Marian Fernandez-Estevez, David C. Rubinsztein
Summary: Acetylation plays a crucial role in neurodegenerative diseases by affecting the clearance and aggregation of proteins, leading to neuron loss and impaired function. Therapeutic targeting of acetylation to restore healthy autophagic activity may have neuroprotective effects in various neurodegenerative diseases. These findings highlight the importance of understanding the role of acetylation in regulating autophagy for the development of potential treatments for neurodegenerative disorders.
EXPERIMENTAL AND MOLECULAR MEDICINE
(2021)
Editorial Material
Cell Biology
Lidia Wrobel, Sandra M. Hill, Avraham Ashkenazi, David C. Rubinsztein
Summary: VCP protein plays a role in promoting autophagosome biogenesis by regulating the levels of PtdIns3P, stabilizing autophagy-related proteins through interactions with ATXN3 and the PtdIns3K complex.
Article
Biochemistry & Molecular Biology
Sandra M. Hill, Lidia Wrobel, Avraham Ashkenazi, Marian Fernandez-Estevez, Keith Tan, Roland W. Burli, David C. Rubinsztein
Summary: VCP is a key regulator in the early initiation of autophagy, playing a role in stabilizing Beclin-1 levels and regulating the activity of the PI3K complex to increase the production of the signaling lipid PI(3)P. Decreased VCP levels or inhibition of its ATPase activity impairs autophagosome formation by limiting downstream recruitment of essential autophagy factors.
NATURE CHEMICAL BIOLOGY
(2021)
Article
Multidisciplinary Sciences
Mariana Pavel, So Jung Park, Rebecca A. Frake, Sung Min Son, Marco M. Manni, Carla F. Bento, Maurizio Renna, Thomas Ricketts, Fiona M. Menzies, Radu Tanasa, David C. Rubinsztein
Summary: This study reveals that autophagy can have opposing effects on the regulation of YAP/TAZ, depending on cellular context, due to a negative feedback loop involving alpha-catenin.
NATURE COMMUNICATIONS
(2021)
Article
Cell Biology
Cansu Karabiyik, Mariella Vicinanza, Sung Min Son, David C. Rubinsztein
Summary: In response to glucose starvation, ULK1 activation by AMPK phosphorylates PIKfyve on S1548, leading to increased synthesis of the phospholipid PI(5)P and formation of PI(5)P-containing autophagosomes. This ULK1-mediated process enhances autophagy flux and reduces autophagy substrate levels.
DEVELOPMENTAL CELL
(2021)
Review
Biochemistry & Molecular Biology
Mariana Pavel, Radu Tanasa, So Jung Park, David C. Rubinsztein
Summary: Autophagy and YAP1-WWTR1/TAZ signaling are tightly linked, with distinct posttranslational modifications dominating these pathways in different cells. The study suggests that understanding these modifications is crucial for developing cell type-specific therapeutic strategies for cancers and other diseases.
Article
Biochemistry & Molecular Biology
So Jung Park, Rebecca A. Frake, Cansu Karabiyik, Sung Min Son, Farah H. Siddiqi, Carla F. Bento, Peter Sterk, Mariella Vicinanza, Mariana Pavel, David C. Rubinsztein
Summary: Autophagy decreases in aging mammalian brains, possibly mediated by increasing levels of vinexin. Knockdown of the SORBS3 gene can promote autophagy.
CELL DEATH AND DIFFERENTIATION
(2022)
Editorial Material
Cell Biology
Claudia Puri, David C. Rubinsztein
Summary: This review discusses a study by Li et al. on the complex mechanism of autophagosome biogenesis, focusing on a new type of ERGIC-ERES membrane contact. The study attempts to reconcile their findings with the proposal that the recycling endosome is a core platform for autophagosome biogenesis.
Review
Neurosciences
Angeleen Fleming, Mathieu Bourdenx, Motoki Fujimaki, Cansu Karabiyik, Gregory J. Krause, Ana Lopez, Claudia Puri, Aurora Scrivo, John Skidmore, Sung Min Son, Eleanna Stamatakou, Lidia Wrobel, Ye Zhu, Ana Maria Cuervo, David C. Rubinsztein
Summary: Autophagy is crucial for maintaining cellular homeostasis by degrading proteins and organelles. The nervous system is particularly dependent on these pathways, which may become less effective with age. Autophagy pathways play a protective role in neurodegenerative diseases and are also linked to different types of programmed cell death.
Article
Multidisciplinary Sciences
Lidia Wrobel, Sandra M. Hill, Alvin Djajadikerta, Marian Fernandez-Estevez, Cansu Karabiyik, Avraham Ashkenazi, Victoria J. Barratt, Eleanna Stamatakou, Anders Gunnarsson, Timothy Rasmusson, Eric W. Miele, Nigel Beaton, Roland Bruderer, Yuehan Feng, Lukas Reiter, M. Paola Castaldi, Rebecca Jarvis, Keith Tan, Roland W. Buerli, David C. Rubinsztein
Summary: Enhancing the removal of aggregate-prone toxic proteins is a rational therapeutic strategy for neurodegenerative diseases, and activating VCP protein can improve the clearance of such proteins through autophagy and proteasome pathways.
NATURE COMMUNICATIONS
(2022)
Article
Cell Biology
Lars Schlotawa, Ana Lopez, Gentzane Sanchez-Elexpuru, Sylwia D. Tyrkalska, David C. Rubinsztein, Angeleen Fleming
Summary: Much of our understanding of the regulation of macroautophagy/autophagy comes from in vitro studies, and there is still a lack of knowledge about its regulation in different tissues in vivo. Upregulation of autophagy is considered a promising therapeutic strategy, so it is important to understand its function in different tissues through in vivo analysis. To achieve this, an inducible expression system has been developed in zebrafish to up- or downregulate autophagy, allowing the investigation of how cell- or tissue-specific changes in autophagic flux affect processes such as aging, inflammation, and neurodegeneration.
Article
Neurosciences
Beatrice Paola Festa, Farah H. Siddiqi, Maria Jimenez-Sanchez, Hyeran Won, Matea Rob, Alvin Djajadikerta, Eleanna Stamatakou, David C. Rubinsztein
Summary: In neurodegenerative diseases, activated microglia secrete pro-inflammatory factors, disrupting neuronal autophagy and protein clearance. The microglia-derived CCL-3/-4/-5 activate neuronal CCR5, leading to mTORC1 activation and autophagy dysfunction. Upregulation of CCR5 and its chemokines in mouse models suggests their role in the early phases of Huntington's disease (HD) and tauopathy. Inhibiting CCR5 can rescue autophagy dysfunction and improve HD and tau pathologies in mouse models.
Article
Cell Biology
Beatrice Paola Festa, Farah H. Siddiqi, Maria Jimenez-Sanchez, David C. Rubinsztein
Summary: In the prodromal phase of neurodegenerative diseases, microglia switch to an activated state and secrete pro-inflammatory factors. These factors, namely CCL3, CCL4, and CCL5, inhibit neuronal autophagy through CCR5 activation, leading to the accumulation of aggregate-prone proteins in neurons. Increased levels of CCR5 and its chemokine ligands are observed in pre-manifesting Huntington disease and tauopathy mouse models. Inhibiting CCR5 rescues mTORC1-autophagy dysfunction and improves neurodegeneration, indicating that CCR5 hyperactivation drives the progression of these diseases.
Review
Biochemistry & Molecular Biology
Michael Takla, Swati Keshri, David C. Rubinsztein
Summary: TFEB is a critical transcription factor involved in multiple physiological functions. Pathological states modify TFEB function by regulating its post-translational modifications, which can have both protective and deleterious effects on tissue survival. Understanding the post-translational modifications of TFEB is important for the development of diseases such as neurodegeneration and cancer.
Article
Cell Biology
Claudia Puri, David C. Rubinsztein
Summary: Using superresolution structured illumination microscopy and electron microscopy, researchers have found that mammalian autophagosomes derive from finger-like outgrowths from the recycling endosome. These fingers close into a fist and the openings are sealed in an ESCRT-dependent fashion. The scission of the autophago-dome liberates free autophagosomes from this compartment, revealing unexpected morphologies of autophagosome precursors and raising new questions about the control of this process.