Article
Biochemistry & Molecular Biology
Yui Jin, Natsuko Jin, Yu Oikawa, Ron Benyair, Michiko Koizumi, Thomas E. Wilson, Yoshinori Ohsumi, Lois S. Weisman
Summary: The vacuole/lysosome plays a crucial role in cell growth and cell cycle progression via the TORC1 pathway. Bur1, an essential cyclin-dependent kinase, cooperates with TORC1 to regulate cell cycle progression, with mutations in BUR1 showing synthetic growth defects and high sensitivity to rapamycin. Together, Bur1 and TORC1 are required for the activation of Sch9 to promote cell cycle progression.
Article
Biology
Ryan L. Wallace, Eric Lu, Xiangxia Luo, Andrew P. Capaldi
Summary: Previous studies have identified mechanisms by which TORC1 is activated by nitrogen and amino acid signals, but it is still unclear how other proteins/pathways regulate TORC1 in simple eukaryotes like yeast. This study discovered a previously uncharacterized GPCR-like protein, Ait1, which binds to TORC1-Gtr1/2 in yeast and regulates TORC1 activity. Under amino acid starvation, Ait1 inhibits TORC1 activity by interacting with Gtr1/2, similar to how the human protein SLC38A9 interacts with RagA/C.
Article
Biochemistry & Molecular Biology
Biao Wang, Wei He, Philipp P. Prosseda, Liang Li, Tia J. Kowal, Jorge A. Alvarado, Qing Wang, Yang Hu, Yang Sun
Summary: This study reveals the crucial role of OCRL in nutrient sensing by showing its localization at the centrosome and recruitment of microtubule-anchoring factor SSX2IP. Deficiency of OCRL leads to loss of microtubule-organizing centers and mTORC1 inactivation, resulting in impaired nutrient sensing. Targeted restoration of microtubule anchoring and mTOR activity can rescue the nutrient sensing ability of cells in Lowe syndrome patients. These findings highlight mTORC1 as a potential therapeutic target for Lowe syndrome.
Article
Multidisciplinary Sciences
Katrin Strassburger, Marilena Lutz, Sandra Mueller, Aurelio A. Teleman
Summary: The size of Drosophila wing discs is determined by the hormone ecdysone through a TORC1-dependent mechanism, with most cells stopping proliferation when the organ reaches the correct size. Reactivation of TORC1 can bypass the termination of proliferation, indicating its role as a main effector in regulating growth arrest at the maximal ecdysone-dependent size. Manipulation of Dpp or Yki signaling can affect proliferation termination in different regions of the wing disc.
NATURE COMMUNICATIONS
(2021)
Article
Multidisciplinary Sciences
Shuo Luo, Xin Wang, Meirong Bai, Wei Jiang, Zhe Zhang, Yifan Chen, Dengke K. Ma
Summary: The study reveals that TMEM39A protein regulates lysosome distribution and accumulation, which is associated with autoimmune diseases. In C. elegans, loss of tmem-39 affects mTOR signaling and activates the HLH-30 transcription factor. TMEM39 family proteins play evolutionarily conserved roles in lysosome distribution and signaling.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Multidisciplinary Sciences
Athena Jessica S. Ong, Cerys E. Bladen, Tara A. Tigani, Anthony P. Karamalakis, Kimberley J. Evason, Kristin K. Brown, Andrew G. Cox
Summary: The maintenance of redox and metabolic homeostasis is crucial for embryonic development. The transcription factor NRF2 plays a central role in regulating redox balance and cellular metabolism and is repressed by KEAP1 under normal conditions. In this study, we show that loss of Keap1 leads to activation of Nrf2 and postdevelopmental lethality due to severe liver abnormalities characterized by an accumulation of lysosomes. We also demonstrate that loss of Keap1 promotes aberrant activation of transcription factors TFEB and TFE3, resulting in lysosomal biogenesis. The findings highlight the importance of the KEAP1-NRF2 pathway in regulating lysosomal homeostasis during embryonic development.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Cell Biology
Julian M. Carosi, Leanne K. Hein, Mark van den Hurk, Robert Adams, Bridget Milky, Sanjna Singh, Cedric Bardy, Donna Denton, Sharad Kumar, Timothy J. Sargeant
Summary: The autophagy-lysosome axis is crucial for the clearance of MAPT aggregates, with dysfunction of the central retromer component VPS35 leading to impaired autophagic resolution and accumulation of cytoplasmic MAPT aggregates. Maintaining the integrity of the retromer complex regulates the autophagy-lysosome axis to suppress MAPT aggregation and propagation.
Article
Cell Biology
Hong Huang, Qinqin Ouyang, Kunrong Mei, Ting Liu, Qiming Sun, Wei Liu, Rong Liu
Summary: This study reveals that both acetylation and phosphorylation modifications control the function of SCFD1 in autophagosome-lysosome fusion. KAT2B/PCAF catalyzes the acetylation of SCFD1, while SIRT4 deacetylates it. Additionally, AMPK-controlled phosphorylation disrupts the interaction between SCFD1 and KAT2B and inhibits SCFD1 acetylation. Furthermore, SCFD1 acetylation inhibits autophagic flux by blocking SNARE complex formation.
Article
Medicine, Research & Experimental
Jacqueline Morales, David Allegakoen, Jose A. Garcia, Kristen Kwong, Pushpendra K. Sahu, Drew A. Fajardo, Yue Pan, Max A. Horlbeck, Jonathan S. Weissman, W. Clay Gustafson, Trever G. Bivona, Amit J. Sabnis
Summary: The study reveals that loss of GATOR2 complex impairs mTORC1 signaling and cell cycle transition in FOXO1 fusion-positive rhabdomyosarcoma (RMS). Suppression of GATOR2 inhibits tumor growth and favors the outgrowth of cells lacking PAX3-FOXO1. Genetic activation of mTORC1 can compensate for the loss of certain GATOR2 members. RAS mutations can decouple mTORC1 activation from GATOR2, resulting in aa-independent mTORC1 activity in fusion-negative RMS. A bisteric, mTORC1-selective small molecule induces tumor regressions in fusion-positive patient-derived tumor xenografts.
Article
Biochemistry & Molecular Biology
Enrico Castroflorio, Joery den Hoed, Daria Svistunova, Mattea J. Finelli, Alberto Cebrian-Serrano, Silvia Corrochano, Andrew R. Bassett, Benjamin Davies, Peter L. Oliver
Summary: Members of the Tre2/Bub2/Cdc16 (TBC), lysin motif (LysM), domain catalytic (TLDc) protein family are associated with neurodevelopmental disorders, including NCOA7 linked to autism. NCOA7 is shown to regulate the function of the vacuolar (V)-ATPase in the brain, with its deletion resulting in neuronal developmental defects and lysosomal dysfunction. Behavioral assessment of Ncoa7 deletion mice revealed anxiety and social defects, indicating the importance of NCOA7 in neurodevelopment.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2021)
Article
Multidisciplinary Sciences
Xiwang Yang, Ya Wen, Shaomin Liu, Liqiang Duan, Tongfeng Liu, Zhou Tong, Zhuo Wang, Yinmin Gu, Yibo Xi, Xiaodong Wang, Dingsan Luo, Ruobing Zhang, Yajuan Liu, Yang Wang, Tianyou Cheng, Siyuan Jiang, Xiaofeng Zhu, Xiaohui Yang, Yongbo Pan, Shuwen Cheng, Qinong Ye, Jinfei Chen, Xiaoding Xu, Shan Gao
Summary: The study revealed the critical role of a long noncoding RNA LCDR in regulating lysosome function, which affects lung cancer cell survival. LCDR interacts with hnRNP K to maintain lysosomal membrane integrity, leading to lysosomal cell death and apoptosis. Targeting LCDR/hnRNP K/LAPTM5 axis may provide potential therapeutic targets for cancer treatment.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Review
Biochemistry & Molecular Biology
Olga Amaral, Mariana Martins, Ana Rita Oliveira, Ana Joana Duarte, Ines Mondragao-Rodrigues, M. Fatima Macedo
Summary: Since its discovery in 1955, the understanding of the lysosome has significantly deepened. It is now recognized as a crucial component for cellular signaling and energy metabolism, challenging the previous perception of it being solely a waste removal system. A summarized review of lysosome biology is necessary to comprehend its role in lysosomal disease.
Article
Biochemistry & Molecular Biology
Indranil Basak, Rachel A. Hansen, Michael E. Ward, Stephanie M. Hughes
Summary: Batten disease, particularly the CLN5 form, results from mutations in the CLN5 gene and leads to neurodegeneration. Research on CLN5-deficient human neurons has shown defects in lysosomes and impaired lysosomal movement, shedding light on the underlying lysosomal pathology in neurodegenerative diseases.
Article
Medicine, Research & Experimental
Weili Fu, Minghao Ge, Jian Li
Summary: The study reveals protein and metabolite alterations in gouty arthritis, which mainly involve lipids, phospholipase A2, and autophagic lysosomes. This research has important implications for understanding the pathological characteristics, pathways, and treatment goals of gouty arthritis.
JOURNAL OF TRANSLATIONAL MEDICINE
(2023)
Article
Multidisciplinary Sciences
Yingbiao Zhang, Chun-Yuan Ting, Shu Yang, John Reich, Karenne Fru, Mary A. Lilly
Summary: It is found that Wdr59 has a dual function in TORC1 regulation in different cellular contexts, promoting or inhibiting TORC1 activity.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Genetics & Heredity
Youheng Wei, Brad Reveal, Weili Cai, Mary A. Lilly
G3-GENES GENOMES GENETICS
(2016)
Article
Genetics & Heredity
Michael D. Rotelli, Robert A. Policastro, Anna M. Bolling, Andrew W. Killion, Abraham J. Weinberg, Michael J. Dixon, Gabriel E. Zentner, Claire E. Walczak, Mary A. Lilly, Brian R. Calvi
Article
Cell Biology
Junmeng Xi, Jiadong Cai, Yang Cheng, Yuanyuan Fu, Wanhong Wei, Zhenbo Zhang, Ziheng Zhuang, Yue Hao, Mary A. Lilly, Youheng Wei
Article
Biology
Youheng Wei, Lucia Bettedi, Chun-Yuan Ting, Kuikwon Kim, Yingbiao Zhang, Jiadong Cai, Mary A. Lilly
Article
Cell Biology
Shu Yang, Yingbiao Zhang, Chun-Yuan Ting, Lucia Bettedi, Kuikwon Kim, Elena Ghaniam, Mary A. Lilly
DEVELOPMENTAL CELL
(2020)
Article
Biology
Yang Cheng, Jiadong Cai, Yuanyuan Fu, Congjing Feng, Yue Hao, Youheng Wei
Article
Cell Biology
Ying Zhou, Jian Guo, Xinyu Wang, Yang Cheng, Jianwen Guan, Priyam Barman, Ming-An Sun, Yuanyuan Fu, Wanhong Wei, Congjing Feng, Mary A. Lilly, Youheng Wei
Summary: The study identified multiple pathways regulating the expression of the GATOR1 component Nprl3 in Drosophila, and highlighted the crucial role of FKBP39 in controlling cellular metabolism.
CELL DEATH & DISEASE
(2021)
Article
Entomology
Xinyu Wang, Ying Zhou, Jianwen Guan, Yang Cheng, Yingying Lu, Youheng Wei
Summary: The study reveals the high expression of FKBP39 and its role in controlling JH activity in fruit flies. In addition, it is shown that FKBP39 regulates the expression of the rp49 gene, potentially affecting ribosome assembly.
Article
Multidisciplinary Sciences
Yingbiao Zhang, Chun-Yuan Ting, Shu Yang, John Reich, Karenne Fru, Mary A. Lilly
Summary: It is found that Wdr59 has a dual function in TORC1 regulation in different cellular contexts, promoting or inhibiting TORC1 activity.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Cell Biology
Ying Zhou, Jianwen Guan, Guoqiang Meng, Weikang Fan, Churui Ge, Chunmei Niu, Yang Cheng, Yuanyuan Fu, Yingying Lu, Youheng Wei
Summary: Preserving female fertility is crucial for animal reproduction under unfavorable conditions. In Drosophila, inhibition of TORC1 is necessary for the maintenance of young egg chambers during nutrient starvation. Knocking down RagA leads to the death of young egg chambers independent of TORC1 hyperactivity. RagA RNAi ovaries exhibit defects in autolysosomal acidification and degradation, making them susceptible to autophagosome augmentation. Additionally, RagA RNAi ovaries show nuclear localization of Mitf, which promotes autophagic degradation and protects young egg chambers under stress.